JP2018536681A - Inhibitors of influenza virus replication, methods of application and use thereof - Google Patents

Abstract

  The present invention provides a new class of compounds as inhibitors of influenza virus replication, methods for their preparation, pharmaceutical compositions comprising these compounds, and the use of these compounds and their pharmaceutical compositions in the treatment of influenza.

Description

Related applications

  This application is subject to the priority of Chinese Patent Application No. 201501083329.2 filed with the National Intellectual Property Office of the People's Republic of China on December 9, 2015, the entire contents of which are incorporated herein by reference. Insist on profit.

Field of Invention

  The present invention belongs to the field of medicine, and specifically, novel compounds used as inhibitors of influenza virus replication, methods for their preparation, pharmaceutical compositions containing these compounds, and these compounds in influenza treatment and their It relates to the use of the pharmaceutical composition. More specifically, the compounds of the present invention can be used as inhibitors of influenza virus RNA polymerase.

background

  Influenza is an acute respiratory infectious disease that is harmful to human health and is caused by influenza viruses, characterized by high morbidity, widespread, and rapid transmission. Influenza viruses can cause severe symptoms in older adults and children with a weak immune system and in immunocompromised individuals such as pneumonia or cardiopulmonary dysfunction. The influenza virus was first discovered by British Wilson Smith, who called the influenza virus H1N1. H means hemagglutinin, N means neuraminidase, and the numbers represent different types. Influenza viruses have caused multiple global pandemics since their discovery, and influenza virus outbreaks occur approximately every 10 years, causing enormous losses worldwide. Influenza occurs annually around the world, resulting in about 250,000 to 500,000 deaths, about 3 million to 5 million severe illnesses, and a total of about 5% to 15% of people worldwide are infected. Yes. Each time, the pandemic is due to the emergence of new strains in humans. These new strains are usually caused by the transmission of existing influenza viruses from other animal species to humans.

  Influenza virus is an RNA virus belonging to the family Orthomyxoviridae belonging to the genus of influenza virus. Influenza viruses are classified into three types, A, B, and C, according to differences in antigenic and genetic properties of virion nucleoprotein (NP) and matrix protein (M). The three types of influenza viruses have similar biochemical and biological characteristics. Viral particles are 80-120 nanometers in diameter and are usually nearly spherical, but can also form filamentous forms. The virus is composed of three layers, the inner layer being a viral nucleocapsid that contains nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen) having type specificity and antigen stability. P proteins (P1, P2, P3) may be polymerases required for RNA transcription and replication. The intermediate viral envelope consists of a layer of lipoid and membrane protein (MP), which has antigen stability and type specificity. The outer layer is a radial ridge composed of two different glycoprotein overhangs, namely hemagglutinin (H) and neuraminidase (N). H is a tool for adsorption of viruses onto sensitive cell surfaces that can cause erythrocyte aggregation, and N is a tool to leave the cell surface after virus replication is complete, which is cell surface specific It is possible to hydrolyze mucus proteins and N-acetylneuraminic acid located at the end of the target glycoprotein receptor. Both H and N have mutating properties and only have strain-specific antigens, their antibodies have a protective effect.

  Influenza virus A has one species, the influenza A virus. Wild aquatic birds are a natural host of a wide variety of influenza A. Sometimes the virus is transmitted to other species, resulting in a catastrophic outbreak in poultry or causing a human influenza pandemic. Type A viruses are the most virulent human pathogens of the three influenza types, causing the most serious diseases and being able to spread to other species, resulting in a human influenza epidemic. Influenza A viruses can be subdivided into different serotypes based on antibody responses to these viruses. Serotypes identified in humans are ordered by the number of known human epidemic deaths, H1N1, which caused Spanish cold in 1918, H2N2, which caused Asian cold in 1957, Hong Kong in 1968 H3N2, which caused a cold, H5N1, which caused a pandemic threat during the 2007-2008 influenza pandemic, H7N7 with the potential for an unusual zoonotic disease, H1N2, an endemic species of humans and pigs, and H9N2, H7N2, H7N3, and H10N7.

  Influenza virus B has one species, the influenza B virus, which causes a regional epidemic influenza and cannot cause a global influenza pandemic. The only animals known to be susceptible to influenza B infection are humans and sea lions. This type of influenza mutates at a rate 2-3 times slower than type A, resulting in poor genetic diversity and only one influenza B serotype. As a result of this lack of antigen diversity, some immunity against influenza B is usually acquired early. However, influenza B is mutated to such an extent that it is impossible to sustain immunity. This reduced rate of antigen change, coupled with its limited host range (which inhibits antigenic variation between species), ensures that an influenza B pandemic does not occur.

  Influenza virus C has one species, influenza C virus, is present in sporadic form, and usually causes only mild disease in children. Influenza virus C usually cannot cause an influenza pandemic and infects humans and pigs.

  Unusually in viruses, the genome contains 7 or 8 segmented segmented negative-strand RNA rather than a single segment of nucleic acid. Influenza A virus genomes include hemagglutinin (H), neuraminidase (N), nucleoprotein (N), M1, M2, NS1, NS2 (NEP), PA, PB1 (polymerase basic 1), PB1-F2 and PB2. 11 proteins are encoded. Hemagglutinin (H) and neuraminidase (N) are the two large glycoproteins outside the viral particle. HA is a lectin that mediates virus binding to target cells and entry of the viral genome into target cells, whereas NA is a measure of progeny virus from infected cells by cleaving sugars that bind to mature virus particles. Involved in release. These proteins are therefore targets for antiviral drugs. Furthermore, they are antigens and antibodies against them can be produced. Influenza A viruses are classified into subtypes based on antibody responses to H and N. These different types of HA and NA form the basis for H and N distinction, for example in H5N1.

  Vaccination and the use of antiviral drugs are important tools for responding to the influenza pandemic. Due to the high mutation rate of influenza virus antigens, vaccines cannot be produced in large quantities before the influenza pandemic. The two classes of antiviral drugs used against influenza are M2 protein inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir and laninamivir). However, influenza viruses have acquired drug resistance against all these drugs. Therefore, there is a continuing demand for new anti-influenza therapeutic agents.

  Favipivirir, a novel antiviral agent with a novel mechanism that acts as an antiviral effect by inhibiting RNA polymerase of influenza virus, targeting the inhibition of viral gene replication, has been launched, but its therapeutic effect and drug resistance of influenza virus There is still a need to be proven. Therefore, there was still a need to study other compounds as anti-influenza drugs of this mechanism.

  The present invention discloses a novel class of compounds used as inhibitors of influenza virus RNA polymerase. These compounds and compositions thereof can be used in the manufacture of a medicament for preventing, treating, treating or reducing a viral infection in a diseased body.

  In one aspect, the present specification includes a compound having the formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. Drag is provided.

In the formula, R ¹ , R ² , R ³ , X, m and n are as defined in the present specification.

In certain embodiments, each R ¹ and R ³ is independently H, F, Cl, Br, CN, NO ₂ , —C (═O) R ^a , —C (═O) OR ^b , —C ( ═O) NR ^c R ^d , OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N—C _1-4 alkylene, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _{1- 4} alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl or (5 to 10 membered heteroaryl) -C _1-4 alkylene. _{wherein, C 1-6} alkyl C _{2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8} cycloalkyl _{-C 1-4} alkylene, from 3-membered to 12-membered heterocyclyl, heterocyclyl to 12-membered (3- ) —C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl and (5 to 10 membered heteroaryl) —C ₁ Each _-4 alkylene is independently unsubstituted or F, Cl, Br, CN, OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O Substituted with one, two, three or four substituents independently selected from —C _1-4 alkylene or R ^d R ^c N—C _1-4 alkylene;
n is 0, 1, 2 or 3;
Each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (from 3 membered 12-membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 membered heteroaryl, (5 to 14 membered heteroaryl) Aryl) -C _1-4 alkylene, or two adjacent R ^{2 s} , together with the atoms to which they are attached, a C _3-12 carbocyclic ring, 3 to 12 membered heterocycle Forming a formula ring, a C _6-10 aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkyl Rene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 Up to 6-membered heteroaryl, (5- to 14-membered heteroaryl) -C _1-4 alkylene, C _3-12 carbocyclic ring, 3 to 12-membered heterocyclic ring, C _6-10 aromatic Each of the ring and 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that When m is 1, R ² is not F,
Each R ′ is independently F, Cl, Br, CN, NO ₂ , oxo (═O), OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N— C _1-4 alkylene, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , C _1-10 alkyl, C _1-6 haloalkyl, C _{3− 6} cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 6 membered heteroaryl or (5 to 6 membered heteroaryl) -C _1-4 alkylene, wherein C _1-10 alkyl, C _{1-6 haloalkyl, C 3-6} cycloalkyl , _{C 3-6} cycloalkyl _{-C 1-4} alkylene, heterocyclyl from 3-membered to 6-membered, (from 3-membered to 6-membered _{heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10} Each of aryl-C _1-4 alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl) -C _1-4 alkylene is independently unsubstituted or F , Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O—C _1-4 alkylene or R ^d R ^c N—C _{1 —} Substituted with 1, 2, 3 or 4 substituents independently selected from ₄ alkylene;
m is 1 or 2,
X is the following sub-formula:

One of
Wherein R ⁴ is H or C _1-6 alkyl, and the C _1-6 alkyl may be optionally substituted with 1, 2, 3, or 4 U;
Each R ⁵ , R ⁶ , R ⁷ and R ⁸ is independently H or C _1-6 alkyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached, C _{3 A -8} cycloalkyl group, a 3 to 6 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring, or R ⁷ and R ⁸ are Together with the nitrogen atom to which it is attached, it forms a 3- to 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, C _1-6 alkyl, C _3-8 cycloalkyl, 3 Each of the 6 to 6 membered heterocyclic ring, the C _6-10 aromatic ring or the 5 to 10 membered heteroaromatic ring is independently unsubstituted or 1, 2, 3 , Or 4 U's,
W is a C _3-12 carbocyclic ring or a 3 to 12 membered heterocyclic ring;
Each V and V ′ is independently a C _3-12 cycloalkane ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring;
Each R ^w is independently F, Cl, Br, CN, NO ₂ , oxo (═O), —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR. _{^{c R d, -S (= O}} ) 2 R e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, (R b O) 2 P (═O) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, C _1-6 alkyl, 5 member To 6-membered heteroaryl or 5- to 6-membered heterocyclyl, wherein each of C _1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl is Independently, unsubstituted or substituted with 1, 2, 3, or 4 U;
Each U is independently F, Cl, Br, NO ₂ , CN, oxo (═O), N ₃ , OR ^b , —NR ^c R ^d , C _1-6 alkyl or C _1-6 haloalkyl;
Each s and t is independently 0, 1, 2 or 3,
p is 1, 2 or 3; and each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6. Alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _{1 -4} alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene Or R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic ring, wherein C _1-6 alkyl, C _{2- 6 alkenyl, C 2-6} alkyl _{Le, C 3-6 cycloalkyl, C 3-6} cycloalkyl _{-C 1-4} alkylene, heterocyclyl from 3-membered to 6-membered, (from 3-membered to 6-membered _{heterocyclyl) -C 1-4} alkylene, _{C 6 -10} aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene and 3 to 6 membered each heterocyclic ring, independently, either unsubstituted, or _{F, Cl, CN, OH,} NH 2, C 1-6 _{alkyl, C 1-6 haloalkyl, C 1-6} alkoxy or _{C 1} Substituted with 1, 2, 3, or 4 substituents independently selected from _-6 alkylamino.

  In other embodiments, the invention provides a compound having Formula (II), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. About.

In the formula, A, R ¹ , R ³ , X, R ′, n and q are as defined in the present specification.

In other embodiments, A is a C _3-12 carbocyclic ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring; And q is 0, 1, 2, 3, 4 or 5.

In other embodiments, each R ¹ and R ³ is independently H, F, Cl, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^{d 1} , OR ^b , —NR ^c R ^d , C _1-3 alkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl, wherein Each of C _1-3 alkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is independently unsubstituted or F, Cl 1, 2, 3 or 4 substituents independently selected from OR ^b , —NR ^c R ^d , C _1-3 alkyl, C _1-3 haloalkyl or R ^b O—C _1-2 alkylene Has been replaced by

In other embodiments, each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 to 6 membered. Heterocyclyl, (5- to 6-membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl Aryl) -C _1-2 alkylene or two adjacent R ² together with the atoms to which they are attached are C _5-6 carbocyclic rings, 5- to 6-membered heterocycles Forming a formula ring, a benzene ring or a 5- to 6-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 members 6 members Up to heterocyclyl, (5- to 6-membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5 to 6-membered heteroaryl, (from 5 to 6 member Each of the heteroaryl) -C _1-2 alkylene, C _5-6 carbocyclic ring, 5- to 6-membered heterocyclic ring, benzene ring and 5- to 6-membered heteroaromatic ring Is unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is not F.

In other embodiments, each R ′ is independently F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , —C (═O) R ^a , —C (═O) NR. ^{cR d} , C _1-9 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene or 5 to 6 membered hetero Aryl, wherein C _1-9 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-4 alkylene and 5 to 6 member. Each of the heteroaryl up to is independently unsubstituted or from F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , methyl, ethyl, n-propyl or i-propyl Independently selected Substituted with one, two, three, or four selected substituents.

In other embodiments, each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _{1 -3} haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene, or R ^c and R ^d together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring, where methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene and 5 to 6 membered Duplicate Each of the cyclocyclic rings is independently unsubstituted or one independently selected from F, Cl, CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl or methoxy Substituted with 2, 3, or 4 substituents.

  In other embodiments, X is of the following sub-formula:

One of
In the formula, W, V, V ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^w and s are as defined in the present specification.

In other embodiments, W is a C _6-8 carbocyclic ring or a _6-8 membered heterocyclic ring.

In other embodiments, V is a C _3-8 cycloalkane ring, a 3 to 8 membered heterocyclic ring, a benzene ring or a 5 to 6 membered heteroaromatic ring.

In other embodiments, V ′ is a C _3-8 cycloalkane ring, a 3 to 8 membered heterocyclic ring, a benzene ring or a 5 to 6 membered heteroaromatic ring.

In other embodiments, each R ^w is independently F, Cl, Br, CN, NO ₂ , oxo (═O), —C (═O) R ^a , —C (═O) OR ^b , — _{^{C (= O) NR c R}} d, -S (= O) 2 R e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, ( R ^b O) ₂ P (═O) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, methyl, Ethyl, i-propyl, n-propyl, n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyrazolyl, where methyl, ethyl , I-propyl, n-propyl, n-butyl, t-butyl, tetrazo Each of lyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted or 1, 2, 3, or 4 U Has been replaced by

In other embodiments, each U is independently F, Cl, Br, CF ₃ , NO ₂ , CN, oxo (═O), N ₃ , OR ^b , —NR ^c R ^d , methyl, ethyl, i -Propyl, n-propyl, n-butyl or t-butyl.

In other embodiments, A is a C _5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, a benzene ring, a naphthalene ring, or a 5- to 6-membered heteroaromatic ring.

In other embodiments, each R ² is independently F, ethynyl, propynyl, OR ^b , C _3-6 carbocyclyl, 5 to 6 membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, Furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, Isoquinolyl, phenoxytinyl,

Where ethynyl, propynyl, C _3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benz Imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxytinyl,

Each independently is unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is F Absent.

  In other embodiments, X is of the following sub-formula:

One of
In the formula, R ^w , s, and V ′ are as defined in the present specification.

In other embodiments, A is a C _5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole, pyridine, pyrazole, imidazole, benzimidazole, triazole. , Tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene, benzothiophene, pyrazine, pyridazine, pyrimidine, indole, purine, quinoline or isoquinoline.

  In other embodiments, the present invention provides compounds having Formula (III), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, R ¹ , R ² , R ³ , m, n and R ^w are as defined in the present specification.

  In other embodiments, the present invention provides compounds having Formula (IV), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, A, R ¹ , R ³ , R ′, n, q and R ^w are as defined in the present specification.

  In other embodiments, the invention provides compounds having Formula (V), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, R ¹ , R ² , R ³ , m, n and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VI), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, A, R ¹ , R ³ , R ′, n, q and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, R ¹ , R ² , R ³ , m, n, s, V ′ and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VIII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, A, R ¹ , R ³ , R ′, n, q, s, V ′ and R ^w are as defined in the present specification.

  In one aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein.

  In certain embodiments, the pharmaceutical compositions provided herein further comprise a pharmaceutically acceptable carrier, adjuvant, vehicle or combination thereof.

  In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents.

  In other embodiments, the therapeutic agent disclosed herein is an anti-influenza virus agent or an anti-influenza virus vaccine.

  In other embodiments, the pharmaceutical composition is in the form of a liquid, solid, semi-solid, gel or spray.

  In other embodiments, the pharmaceutical composition disclosed herein, wherein the therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, albidol , Ribavirin, stachyfurin, ingavirin, Fludase, CAS number 14222050-75-6, JNJ-872, AL-794, influenza vaccine (FluMist Quadrivent (R), Fluorix (R) Quadrivent, Fluzone (R) vxr (R) vx (Registered trademark) or FluBlok (registered trademark)) or a combination thereof.

  In other aspects, provided herein are compounds or compounds disclosed herein in the manufacture of a medicament for preventing, treating, treating, or alleviating a disorder or disease resulting from a viral infection in a subject. Use of the pharmaceutical composition is provided.

  In certain embodiments, the viral infection disclosed herein is an influenza virus infection.

  In another aspect, provided herein is the use of a compound or pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting an influenza virus RNA polymerase.

  In other aspects, provided herein are compounds or pharmaceutical compositions disclosed herein for use in preventing, treating, treating, or alleviating a disorder or disease resulting from a viral infection. Is provided.

  In certain embodiments, the viral infection disclosed herein is an influenza virus infection.

  In another aspect, provided herein is a compound or pharmaceutical composition disclosed herein for use in inhibiting an influenza virus RNA polymerase.

  In another aspect, the present specification prevents a disorder or disease resulting from a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. Methods of treating, treating, treating or alleviating are provided.

  In certain embodiments, the viral infection disclosed herein is an influenza virus infection.

  In another aspect, provided herein is a method of inhibiting influenza virus RNA polymerase in a subject comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. Is done.

  Unless otherwise specified, all stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds disclosed herein. Is included in the scope of the present invention.

  In one embodiment, the salt is a pharmaceutically acceptable salt thereof. The phrase “pharmaceutically acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal to be treated thereby. That means.

  In other embodiments, the salt need not be a pharmaceutically acceptable salt, but it may be used for the preparation and / or purification of the compounds of the invention and / or for the separation of enantiomers of the compounds of the invention. Can be useful as an intermediate.

  Furthermore, the compounds disclosed herein (including salts thereof) may be obtained in the form of their hydrates or may contain other solvents used for their crystallization. The compounds of the present invention may form solvates with pharmaceutically acceptable solvents (including water) in essence or intention, and therefore the present invention is solvated forms and unsolvated It is contemplated to include both forms.

  In other embodiments, the compounds disclosed herein may contain several asymmetric centers and therefore exist in the form of a generally described racemic mixture. Furthermore, it is contemplated that all of the racemic mixture, a portion of the racemic mixture, and the enantiomers and diastereomers purified by separation form part of the present invention.

  The compounds disclosed herein may exist in the form of possible isomers, including rotamers, atropisomers, tautomers or mixtures thereof. Rotamers, atropisomers, mixtures of isomers including tautomers, portions of mixtures of isomers, rotamers, atropisomers, tautomers, and rotamers purified by separation, It is contemplated that atropisomers, isomers including tautomers, form part of the present invention.

In other aspects, compounds of the invention include isotopically enriched compounds as defined herein, including those containing radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F, or ² H and Some contain non-radioactive isotopes such as ¹³ C.

  In another aspect, provided herein is a method for preparing, separating, or purifying a compound of formula (I).

  The foregoing merely summarizes the specific aspects disclosed herein and is not intended to be limiting. These and other aspects and embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION Definitions and General Terminology Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. One or more of the incorporated literature, patents and similar materials may differ from or contradict with the present application, including but not limited to defined terms, use of terms, described techniques, etc. In this case, this application will control.

  Furthermore, it will be appreciated that certain features of the invention described in the context of alternative embodiments for clarity may be provided in combination in a single embodiment. Conversely, the various features of the invention described in the context of a single embodiment for convenience may be provided separately or in any suitable sub-combination.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

  As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table CAS version of the elements and the Handbook of Chemistry and Physics, 75th Ed. 1994. In addition, the general principles of organic chemistry are: Sorrell et al., “Organic Chemistry”, University Science Books, Sausalito: 1999, and Michael B. Smith et al., “March's Advanced Organic Chemistry”, John Wiley & Sons, New York : 2007, the entire contents of which are incorporated herein by reference.

  As used herein, the term “treatment subject” refers to an animal. Typically, the animal is a mammal. The treatment target also refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject to be treated is a primate. In yet other embodiments, the treatment subject is a human.

  The term “treatment subject” may be used interchangeably with “affected subject” in the present invention. The terms “subject” and “affected” refer to animals (eg, birds such as chickens, quails or turkeys, or mammals), particularly mammals including non-primates (eg, cows, pigs, horses, sheep, Rabbits, guinea pigs, rats, dogs, cats and mice) and primates (eg monkeys, chimpanzees and humans), more particularly humans. In some embodiments, the subject to be treated is a non-human animal such as a domestic animal (eg, horse, cow, pig or sheep) or pet (dog, cat, guinea pig or rabbit). In some other embodiments, “affected” refers to a human.

Any formula provided herein is intended to represent isotopically enriched and isotopically enriched forms of the compounds. Isotopically enriched compounds have the structure represented by the formulas given herein, except that one or more atoms are replaced with atoms having a selected atomic weight or mass number. Have. Examples of isotopes that can be incorporated into the compounds of the invention include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁷ Cl, etc. Of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively.

Compounds disclosed herein and pharmaceutical salts thereof containing the aforementioned isotopes or other atomic isotopes and pharmaceutical salts thereof are within the scope of the present invention. Certain isotopically-labelled compounds of the present invention are useful in drug and / or substrate tissue distribution assays, for example those containing a radioactive isotope such as ³ H or ¹⁴ C. For easy purification and detection, isotopes such as tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are preferred. Further, substitution with heavy isotopes, particularly deuterium (ie, ² H or D), may have high metabolic stability, eg, increased half-life or reduced required dosage in vivo, or improved therapeutic index, such as May provide certain therapeutic benefits resulting from an improved in vivo half-life or reduced required dosage, or improved therapeutic index. Thus, heavy isotopes may be preferred in any embodiment.

  The definition and convention of stereochemistry used herein is generally described in SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen. , S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein can contain asymmetric or chiral centers and can therefore exist in different stereoisomers. All stereoisomeric forms of the compounds disclosed herein, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof such as racemic mixtures, are part of this invention. Is contemplated. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (−) are used to indicate the sign of rotation of plane polarized light by the compound, (−) or l means that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. Certain stereoisomers are referred to as enantiomers, and mixtures of such stereoisomers are referred to as enantiomeric mixtures. Certain stereoisomers are referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

  Depending on the choice of starting material and procedure, the compound may exist in one form of possible stereoisomers or as a mixture thereof, such as a racemate or diastereomeric mixture, based on the number of asymmetric carbon atoms. obtain. Optically active (R)-and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. Where the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

  The compounds disclosed herein can contain asymmetric or chiral centers and can therefore exist in different stereoisomers. All stereoisomeric forms of the compounds disclosed herein including, but not limited to, diastereomers, enantiomers and geometric (conformational) isomers, and mixtures thereof such as racemic mixtures It is contemplated to form part of the present invention.

  Unless otherwise specified, the formulas described herein are intended to include all isomers thereof (eg, enantiomers, diastereomers, atropisomers and geometric (conformational) isomers; eg, all (R)-and (S) -isomers, (Z) and (E) isomers around the double bond, (Z) and (E) conformers). Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric isomer mixtures of the present compounds are included within the scope disclosed herein.

  The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. Where tautomerization is possible (eg, in solution), a chemical equilibrium between tautomers is achieved. For example, proton tautomers (also known as prototrophic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the tautomerism of hexane-2,4-dione and 4-hydroxyhex-3-en-2-one. Another example of tautomerism is phenol-keto tautomerization. A specific example of phenol-keto tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one. Unless otherwise stated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

  “N-oxide” refers to one or more nitrogen atoms that are oxidized to form an N-oxide, where the compound comprises several amine functional groups. Particular examples of N-oxides are nitrogenous heterocyclic tertiary amines or N-oxides of nitrogen atoms. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid) (Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley). (See Interscience, pages). More specifically, N-oxides can be made by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which the amine compound is inert, such as for example dichloromethane. React with m-chloroperoxybenzene acid (MCPBA) in a solvent.

  The term “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of some of the solvents that produce solvates include water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to a mixture in which the solvent molecule is water.

  “Metabolite” refers to a product produced by metabolism in the body of a particular compound or salt thereof. A metabolite of a compound can be identified using routine techniques known in the art, and its activity is determined using tests such as those described herein. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, esterolysis, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient amount of time.

“Pharmaceutically acceptable salt” refers to an organic or inorganic salt of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable non-toxic salts include inorganic salts such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid and nitric acid, or acetic acid, oxalic acid, Including salts of amino groups generated with organic acids such as maleic acid, tartaric acid, citric acid, succinic acid and malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoic acid Salt, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2- Naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropiate Including phosphate, picrate, pivalate, propionate, stearate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. This invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products can be obtained by such quaternization. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In addition, pharmaceutically acceptable salts are non-toxic produced with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates or aryl sulfonates where appropriate. Neutral ammonium, quaternary ammonium, and amine cations.

The term “prodrug” refers to a compound that is converted in vivo to a compound of formula (I). Such conversion may be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic conversion to the original form in blood or tissue. Prodrugs of the compounds disclosed herein can be, for example, esters. Some common esters that can be used as prodrugs are phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein containing a hydroxy group can be acylated in its prodrug form at this position. Other prodrug forms include phosphates such as phosphate compounds derived from phosphorylation of the parent compound's hydroxy group. A thorough discussion of prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, all of which are hereby incorporated by reference in their entirety.

  Any asymmetric atom (eg, carbon etc.) of the compounds disclosed herein exists in a racemic or enantiomeric rich state, eg, in the (R), (S) or (R, S) configuration. obtain. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80, in the (R) or (S) configuration. % Enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If the compound contains a double bond, the substituent can be in the cis (Z) or trans (E) configuration.

  Thus, as described in the present invention, the compounds disclosed herein may be rotamers, atropisomers, tautomers, or mixtures thereof, ie, substantially pure geometry (cis or trans). It can exist in any possible stereoisomeric form such as isomers, diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

  Any resulting mixture of stereoisomers can be converted into pure or substantially pure geometric isomers, enantiomers, diastereoisomers, racemates, eg, chromatographic and based on the physicochemical differences of the components. They can be separated by fractional crystallization.

  The resulting racemate, either the final product or the intermediate, can be resolved into the optical antipodes by methods known to those skilled in the art, for example by separation of its diastereoisomeric salts. Racemic products can also be resolved by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. For example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, See EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972). That.

As described herein, a compound disclosed herein can be one or more of the compounds generally exemplified below or as exemplified by certain classes, subclasses and species of the present invention. It may be optionally substituted with a substituent. It will be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or not substituted”. The term “arbitrary” or “arbitrarily” means that an event or situation described subsequently may occur, but does not need to occur, and its description includes the case where the event or situation occurs and This refers to cases that do not occur. In general, replacing one or more hydrogen groups in a given structure with a particular substituent group, whether or not the term “optionally” precedes the term “substituted” Say. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group. If more than one position in a given structure can be substituted with more than one substituent selected from a particular group, the substituents are the same or different at each position. The substituents described herein are not limited, but include F, Cl, Br, CN, N ₃ , OH, NH ₂ , NO ₂ , oxo (═O), —C (═O) R. ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , —S (═O) ₂ R ^e , —S (═O) ₂ NR ^c C (═O) R ^a , − S (═O) ₂ NR ^c R ^d , (R ^b O) ₂ P (═O) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N—C _1-4 alkylene, C _1-6 alkyl, C _1-6 aliphatic group, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _{2-6 alkynyl, C 3-8 cycloalkyl, C 3-8} cycloalkyl _{-C 1-4} alkylene, Heteroshi from 3-membered to 12-membered Lil, _{-C 1-4} alkylene (3 membered heterocyclyl up to _{12-membered), C 6-10 aryl, C 6-10} aryl _{-C 1-4} alkylene, from 5-membered to 14-membered heteroaryl or (5- To 14-membered heteroaryl) -C _1-4 alkylene, where R ^a , R ^b , R ^c , R ^d and R ^e are as defined herein.

  Further, it is necessary to explain that the phrases “each ... independently” and “each of… and…” should be broadly understood unless otherwise indicated. Specific options represented by the same symbol are independent of each other in different groups, or specific options represented by the same symbol are independent of each other in the same group.

At various places in the present specification, substituents of compounds disclosed herein are disclosed in groups or in ranges. The present invention specifically contemplates including each and every individual sub-combination of members of such groups and ranges. For example, the term “C _1-6 alkyl” is specifically contemplated to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

  At various points in the specification, linking substituents have been described. Where the structure clearly requires a linking group, the Markush selected element listed for that group is understood to be a linking group. For example, when a structure requires a linking group and the Markush group definition for the selected element states "alkyl" or "aryl", the "alkyl" or "aryl" is a linking alkylene group, respectively. Or is understood to represent an arylene group.

  The term “alkyl” or “alkyl group” refers to a saturated straight or branched monovalent hydrocarbon group of 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-9 carbon atoms. In other embodiments, the alkyl group contains 1-8 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms. In still other embodiments, the alkyl group contains 1-3 carbon atoms.

Some non-limiting examples of alkyl groups include methyl (Me, _-CH 3), ethyl _{(Et, -CH 2 CH 3)} , n- propyl _{(n-Pr, -CH 2 CH} 2 CH 3), isopropyl _{(i-Pr, -CH (CH} 3) 2), n- butyl _{(n-Bu, -CH 2 CH} 2 CH 2 CH 3), isobutyl _{(i-Bu, -CH 2 CH} (CH 3) 2) , sec- butyl _{(s-Bu, -CH (CH} 3) CH 2 CH 3), tert- butyl _{(-t Bu, -C (CH} 3) 3), n- pentyl _{(-CH 2} CH 2 _CH 2 CH ₂ CH ₃ ), 2-pentyl (—CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (—CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (—C (CH _{3) 2 CH 2 CH 3)} , 3- methyl-2-butyl _{-CH (CH 3) CH (CH} 3) 2), 3- methyl -l- butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl -l- butyl _(-CH 2 CH (CH ₃ ) CH ₂ CH ₃ ), n-hexyl (—CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (—CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl ( _{-CH (CH 2 CH 3) (} CH 2 CH 2 CH 3)), 2- methyl-2-pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl (- _{CH (CH 3) CH (CH} 3) CH 2 CH 3), 4- methyl-2-pentyl _{(-CH (CH 3) CH 2} CH (CH 3) 2), 3- methyl-3-pentyl (-C _{(CH 3) (CH 2 CH} 3) 2), 2- methylcarbamoyl 3- pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl-2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- Including dimethyl-2-butyl (—CH (CH ₃ ) C (CH ₃ ) ₃ , n-heptyl, n-octyl, and the like, wherein the alkyl groups are independently unsubstituted or described herein. It may be substituted with one or more substituents.

  The term “alkyl” or the prefix “alka-” includes both straight and branched saturated carbon chains.

The term “alkylene” refers to a saturated divalent hydrocarbon group derived from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon. Unless otherwise specified, alkylene groups contain 1-10 carbon atoms. In other embodiments, alkylene groups contain 1-6 carbon atoms. In still other embodiments, the alkylene group contains 1-4 carbon atoms. In still other embodiments, the alkylene group contains 1-2 carbon atoms. Such alkylene groups are exemplified by methylene (—CH ₂ —), ethylene (—CH ₂ CH ₂ —), isopropylene (—CH (CH ₃ ) CH ₂ —), and the like. An alkylene group is independently unsubstituted or optionally substituted with one or more substituents described herein.

The term “alkenyl” means at least one unsaturation, ie, 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 having a carbon-carbon, sp ² double bond. To a straight chain or branched monovalent hydrocarbon group of from 2 to 4 carbon atoms, or from 2 to 4 carbon atoms, wherein the alkenyl group is independently unsubstituted or It may be substituted with one or more substituents disclosed herein and includes groups having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations. Examples of alkenyl groups include, but are not limited to, vinyl (—CH═CH ₂ ), allyl (—CH ₂ CH═CH ₂ ), and the like.

The term “alkynyl” refers to at least one site of unsaturation, ie, from 2 to 12 carbon atoms, or from 2 to 8 carbon atoms, or from 2 to 6 carbon-carbon, sp triple bonds. Refers to up to 1 carbon atom or a straight or branched monovalent hydrocarbon group of 2 to 4 carbon atoms, wherein the alkynyl group is independently unsubstituted or Optionally substituted with one or more substituents disclosed in the literature. Examples of alkynyl groups include, but are not limited to, acetenyl (—C≡CH), propargyl (—CH ₂ C≡CH), 1-propynyl (—C≡C—CH ₃ ), and the like.

  The term “alkoxy” refers to an alkyl group, as defined above, attached to the parent molecular group through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1-20 carbon atoms. In one embodiment, the alkoxy group contains 1-10 carbon atoms. In other embodiments, alkoxy groups contain 1-8 carbon atoms. In still other embodiments, the alkoxy group contains 1-6 carbon atoms. In still other embodiments, the alkoxy group contains 1-4 carbon atoms. In yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms.

Some non-limiting examples of alkoxy groups include methoxy (MeO, -OCH _3), ethoxy _{(EtO, -OCH 2 CH 3)} , 1- propoxy (n-PrO, n-propoxy, -OCH ₂ CH ₂ CH _3), 2-propoxy (i-PrO, i- _{propoxy, -OCH (CH 3) 2)} , 1- butoxy (n-BuO, n- _{butoxy, -OCH 2 CH 2 CH 2 CH} 3), 2- methyl -l- propoxy (i-BuO, i- _{butoxy, -OCH 2 CH (CH 3)} 2), 2- butoxy (s-BuO, s- _{butoxy, -OCH (CH 3) CH 2} CH 3), 2 - methyl-2-propoxy (t-BuO, t- _{butoxy, -OC (CH 3) 3)} , 1- pentoxy (n- _{pentoxy, -OCH 2 CH 2 CH 2 CH} 2 CH 3), 2- pent Shi _{(-OCH (CH 3) CH 2} CH 2 CH 3), 3- pentoxy _{(-OCH (CH 2 CH 3)} 2), 2- methyl-2-butoxy _{(-OC (CH 3) 2 CH} 2 CH 3 ), 3-methyl-2-butoxy (—OCH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butoxy (—OCH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1 - containing butoxy _{(-OCH 2 CH (CH 3)} CH 2 CH 3) or the like. Alkoxy groups are independently unsubstituted or substituted with one or more substituents disclosed herein.

  The term “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to an alkyl, alkenyl, alkoxy optionally substituted with one or more halogen atoms. Some non-limiting examples of “haloalkyl”, “haloalkenyl” or “haloalkoxy” groups include trifluoromethyl, trifluoromethoxy, and the like.

  The terms “carbocycle”, “carbocyclyl”, “carbocyclic” or “carbocyclic ring” used interchangeably herein refer to a ring having from 3 to 14 ring carbon atoms, It is saturated or contains one or more unsaturated units. In some embodiments, the number of carbon atoms is from 3 to 12, in other embodiments, the number of carbon atoms is from 3 to 10, and in other embodiments, the number of carbon atoms is 3 to 8, in other embodiments, the number of carbon atoms is 5 to 6, and in other embodiments, the number of carbon atoms is 6 to 8. “Carbocyclyl” means a monocyclic, bicyclic or polycyclic fused ring, spiro ring or bridged ring system and one or more non-aromatic carbocyclic or heterocyclic rings, or one There are groups or points attached on the carbocyclic ring, including polycyclic ring systems containing one carbocyclic ring fused to the above aromatic rings or combinations thereof. Bicyclic carbocyclyl groups include bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spiro bicyclic carbocyclyl groups, and fused bicyclic systems containing two rings sharing two adjacent ring atoms. A bridged bicyclic group includes two rings that share three or four ring atoms next to a ring atom. Spiro bicyclic systems contain two rings that share one ring atom. Some non-limiting examples of carbocyclyl groups include cycloalkyl, cycloalkenyl and cycloalkynyl. Further non-limiting examples of carbocyclyl groups are cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-yl. -Enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Bridged bicyclic carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3. 2.3] Including nonyl and the like.

  The term “cycloalkyl” refers to a saturated ring having from 3 to 12 ring carbon atoms as a monocyclic, bicyclic or tricyclic ring system with one or more connections attached to the rest of the molecule. In some embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms. In other embodiments, cycloalkyl groups contain from 3 to 8 ring carbon atoms. In yet other embodiments, the cycloalkyl group contains 3 to 6 ring carbon atoms. In yet other embodiments, the cycloalkyl group contains from 5 to 6 ring carbon atoms. A cycloalkyl group is independently unsubstituted or substituted with one or more substituents described herein.

The terms “heterocycle”, “heterocyclyl”, or “heterocyclic ring” used interchangeably herein include 3 to 12 ring atoms, at least one of the ring atoms being nitrogen, sulfur or A saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic ring selected from oxygen may have one or more connections attached to the rest of the molecule. The term “heterocyclyl” refers to monocyclic, bicyclic or polycyclic fused, spiro, bridged heterocyclic ring systems, and one or more non-aromatic carbocyclic or heterocyclic rings, or There are groups or connections attached on the heterocyclic ring, including polycyclic ring systems containing one carbocyclic ring fused to one or more aromatic rings, or combinations thereof. Biheterocyclyl groups include bridged biheterocyclyl, fused biheterocyclyl and spirobiheterocyclyl. Unless otherwise specified, heterocyclyl groups can be attached to carbon or nitrogen, and the —CH ₂ — group can be optionally replaced with a —C (═O) — group. There, sulfur may optionally be oxidized to S-oxide, and nitrogen may optionally be oxidized to N-oxide. In some embodiments, the heterocyclyl group is a 3 to 8 membered part or bicyclic heterocyclyl group, and in other embodiments, the heterocyclyl group is a 3 to 6 membered part or bicyclic ring. In other embodiments, the heterocyclyl group is a 6 to 8 membered mono- or bicyclic heterocyclyl group, and in other embodiments, the heterocyclyl group is from 5 to 6 members. Up to a heterocyclyl group, in other embodiments, the heterocyclyl group is a 4-membered heterocyclyl group, in other embodiments, the heterocyclyl group is a 5-membered heterocyclyl group, and in other embodiments, the heterocyclyl group The group is a 6-membered heterocyclyl group, and in other embodiments the heterocyclyl group is a 7-membered heterocyclyl group. A Lil group, in other embodiments, the heterocyclyl group is a heterocyclyl group having 8 membered.

Some non-limiting examples of heterocyclyl groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl Thienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl , Thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, 1,2,3,4-tetrahy Including Roisokinoriru, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl. Some non-limiting examples of heterocyclyl in which the —CH ₂ — group is replaced by a —C (═O) — group include 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3 , 5-dioxopiperidinyl, pyrimidinedione-yl. Some non-limiting examples of heterocyclyl in which the ring sulfur atom has been oxidized are sulfolanyl and 1,1-dioxo-thiomorpholinyl. Some non-limiting examples of bridged heterocyclyl groups include 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl. Etc. A heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.

  The term “bridge” refers to a bond, atom, or unbranched chain connecting two different sites of a molecule. Two atoms connected by a bridge (usually but not always two tertiary carbon atoms) mean a “bridge head”.

  The term “spiro” refers to a ring system containing one atom that is the only shared atom (usually a quaternary carbon) between two rings.

  In the term “n-membered”, n is an integer that is typically described as the number of ring-forming atoms in a group where the number of ring-forming atoms is n. For example, piperidyl is an example of a 6-membered heterocyclyl, and a 1,2,3,4-tetrahydro-naphthyl group is an example of a 10-membered carbocyclyl group.

  The term “heteroatom” refers to any oxidized form of nitrogen, sulfur, or phosphorus, a quaternized form of any basic nitrogen, or a displaceable nitrogen of a heterocyclic ring, such as N (3, Oxygen (O), sulfur (S), nitrogen (N), including as in 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) , Phosphorus (P) and silicon (Si).

  The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term “azido” or “N ₃ ” refers to an azido group. This group is, for example, attached to a methyl group, azidomethyl (Mechiruajido, MeN ₃₎ can form a bond to a phenyl azide (PhN ₃₎ on whether or phenyl group, to form a.

  The term “aryl” used alone or as the majority of “arylalkyl”, “arylalkoxy” means a total of 6 to 14 ring members, or 6 to 12 ring members, or 6 Refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having from 1 to 10 ring members, wherein at least one ring in the system is aromatic and each ring in the system comprises from 3 It contains up to 7 ring members and has one or more binding sites connected to the rest of the molecule. The term “aryl” may be used interchangeably with the term “aryl ring” or “aromatic ring”. Some non-limiting examples of aryl groups include phenyl, naphthyl and anthryl. An aryl group is optionally unsubstituted or optionally substituted with one or more substituents disclosed herein.

The term “heteroaryl” used alone or as the majority of “heteroarylalkyl” or “heteroarylalkoxy” refers to a total of 5 to 14 ring members, or 5 to 12 ring members, Or monocyclic, bicyclic and tricyclic ring systems having from 5 to 10 ring members, or from 5 to 6 ring members, at least one ring in the system being aromatic Yes, at least one ring member is selected from a heteroatom and each ring in the system contains from 5 to 7 ring members and has one or more binding sites connected to the rest of the molecule. Unless otherwise specified, heteroaryl groups can be carbon or nitrogen bonded and the —CH ₂ — group can be optionally replaced with a —C (═O) — group. There, sulfur may optionally be oxidized to S-oxide, and nitrogen may optionally be oxidized to N-oxide. The terms “heteroaryl” and “heteroaromatic ring” or “heteroaromatic compound” may be used interchangeably herein. In one embodiment, the heteroaryl group is a 5- to 12-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 5-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

  Some non-limiting examples of heteroaryl groups include the following monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4 -Pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (eg 2-triazolyl, 5 -Triazolyl, 4H-1,2,4-triazolyl, H-1,2,4-triazolyl and 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, as well as the following two rings: but not limited to benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (eg, 2-indolyl), purinyl, quinolinyl (eg, 2- Quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg, 1-isoquinoyl) Cycloalkenyl, 3- isoquinolinyl, or 4-isoquinolinyl), oxathianyl,

including. A heteroaryl group may be optionally substituted with one or more substituents disclosed herein.

The term “carboxy” or “carboxyl” refers to —CO ₂ H, whether used alone or in combination with other terms such as “carboxyalkyl”. The term “carbonyl” means — (C═O) —, whether used alone or in combination with other terms such as “aminocarbonyl”, “acyloxy”.

The term “alkylamino” refers to “N-alkylamino” and “N, N-dialkylamino”, wherein the amino groups are independently substituted with one alkyl group or two alkyl groups, respectively. . In some embodiments, an alkylamino group is a lower alkylamino group having 1 or 2 C _1-6 alkyl groups bonded to a nitrogen atom. In another embodiment, the alkylamino group is a C _1-3 lower alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.

  The term “arylamino” refers to an amino group substituted with one or two aryl groups. Some non-limiting examples of such groups include N-phenylamino. In some embodiments, the aryl group of arylamino may be further substituted.

The term “aminoalkyl” refers to a C _1-10 straight or branched chain alkyl group substituted with one or two amino groups. In some embodiments, the aminoalkyl is C _1-6 lower aminoalkyl substituted with one or two amino groups. Some non-limiting examples of aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

  As described herein, a bond drawn from a substituent to the center of one ring in the ring system indicates substitution of the substituent at any substitutable position on the ring, and the ring The system includes monocyclic, bicyclic or polycyclic ring systems. For example, Formula a shows substitution of substituents at any substitutable position on the bicyclic ring system of Ring A and Ring B, ie, Formula b-1 to Formula b-8.

  As described herein, a bond drawn from a substituent to the center of one ring in a ring system is a bond that the bond can connect to the rest of the molecule at any bondable position on the ring. Show. For example, formula c shows substitution of substituents at any substitutable position on the ring, ie, formula d-1 and formula d-2.

  The term “unsaturated” refers to a group having one or more units of unsaturation.

  The terms “comprising” or “comprise” are meant to be open and include the indicated components, but do not exclude other elements.

  As described herein, the term “pharmaceutically acceptable carrier” refers to any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (eg, antibacterial agent, antifungal Agents), isotonic agents, salts, drug stabilizers, binders, excipients, dispersants, lubricants, sweeteners, flavorings, colorants or combinations thereof, all of which are well known to those skilled in the art (Eg, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, which is incorporated herein by reference in its entirety). Pharmaceutically acceptable carriers are effectively used in therapeutic or pharmaceutical compositions, except that any conventional carrier is incompatible with the active ingredient.

  As used herein, the term “inhibition of influenza virus replication” refers to a reduction in viral replication (eg, a reduction of at least 10%) and complete arrest of viral replication (ie, 100 viral replication. % Reduction). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

  As used herein, an “effective amount” refers to an amount sufficient to elicit a desired biological response. In the present invention, the desired biological response is to inhibit influenza virus replication, to reduce the amount of influenza virus, or to reduce or improve the severity, duration, progression or onset of influenza virus infection. Preventing the progression of influenza virus infection, preventing the recurrence, development, onset or progression of symptoms associated with influenza virus infection, or the prevention or treatment of another treatment used for influenza infection It is to enhance or improve the effect. The exact amount of the compound administered to the subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject to be treated, such as general health, age, sex, weight and drug resistance. I will. One skilled in the art will be able to determine the appropriate dosage based on these and other factors. When co-administered with other antiviral agents, for example when co-administered with anti-influenza agents, the “effective amount” of the second agent will depend on the type of agent used. Appropriate dosages are known for approved drugs and can be adjusted by those skilled in the art according to the condition of the subject to be treated, the type of disease being treated and the amount of compound used herein. If the amount is not explicitly stated, an effective amount should be assumed. For example, the compounds described herein can be administered to a therapeutic subject at a dose range of about 0.01-100 mg / kg body weight / day for therapeutic or prophylactic treatment.

  As used herein, the terms “treat”, “treatment” and “treating” refer to both therapeutic and prophylactic treatment. For example, therapeutic treatment may include the progression, severity, and severity of influenza virus-mediated disease resulting from the administration of one or more therapeutic agents (eg, one or more therapeutic agents such as compounds or compositions of the invention). Reduction or amelioration of the period, or improvement of one or more symptoms (specifically, one or more identifiable symptoms) of an influenza virus mediated disease. In certain embodiments, the therapeutic treatment comprises an improvement in at least one measurable physical parameter of influenza virus mediated disease. In other embodiments, the therapeutic treatment is, for example, inhibiting the progression of influenza virus-mediated disease physically, eg, by stabilizing identifiable symptoms, eg, physiologically, by stabilizing physical parameters, or both. including. In other embodiments, the therapeutic treatment includes reduction or stabilization of influenza virus mediated infection. Antiviral drugs can be used in social environments to treat people who already have influenza, reduce the severity of symptoms, and reduce the number of days they are ill.

The term “protecting group” or “PG” refers to substituents commonly used to block or protect a particular functionality while reacting with other functional groups of the compound. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, “hydroxy protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. “Carboxy protecting group” refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting _{groups, -CH 2 CH 2 SO 2 Ph} , cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl - methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p- Nitrophenylsulfonyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF COMPOUNDS OF THE INVENTION The present invention discloses novel compounds for use as inhibitors of influenza virus replication and influenza virus RNA polymerase. These compounds and compositions thereof can be used as therapeutic agents for preventing, treating, treating, or alleviating viral infections in affected subjects.

  In one aspect, the present specification includes a compound having the formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. A drag is provided,

In the formula, R ¹ , R ² , R ³ , X, m and n are as defined in the present specification.

In certain embodiments, each R ¹ and R ³ is independently H, F, Cl, Br, CN, NO ₂ , —C (═O) R ^a , —C (═O) OR ^b , —C ( ═O) NR ^c R ^d , OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N—C _1-4 alkylene, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _{1- 4} alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl or (5 to 10 membered heteroaryl) -C _1-4 alkylene. _{wherein, C 1-6} alkyl C _{2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8} cycloalkyl _{-C 1-4} alkylene, from 3-membered to 12-membered heterocyclyl, heterocyclyl to 12-membered (3- ) —C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl and (5 to 10 membered heteroaryl) —C ₁ Each _-4 alkylene is independently unsubstituted or F, Cl, Br, CN, OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O— Substituted with one, two, three or four substituents independently selected from C _1-4 alkylene or R ^d R ^c N—C _1-4 alkylene;
n is 0, 1, 2 or 3;
Each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (from 3 membered 12-membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 membered heteroaryl, (5 to 14 membered heteroaryl) Aryl) -C _1-4 alkylene, or two adjacent R ^{2 s} , together with the atoms to which they are attached, a C _3-12 carbocyclic ring, 3 to 12 membered heterocycle Forming a formula ring, a C _6-10 aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkyl Rene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 Up to 6-membered heteroaryl, (5- to 14-membered heteroaryl) -C _1-4 alkylene, C _3-12 carbocyclic ring, 3 to 12-membered heterocyclic ring, C _6-10 aromatic Each of the ring and 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is not F;
Each R 'is independently, F, Cl, Br, CN , NO 2, oxo ^{(= O), OR b,} -NR c R d, R b O-C 1-4 ^alkylene, R ^d R c N- C _1-4 alkylene, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , C _1-10 alkyl, C _1-6 haloalkyl, C _{3− 6} cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 6 membered heteroaryl or (5 to 6 membered heteroaryl) -C _1-4 alkylene, wherein C _1-10 alkyl, C _{1-6 haloalkyl, C 3-6} cycloalkyl , _{C 3-6} cycloalkyl _{-C 1-4} alkylene, heterocyclyl from 3-membered to 6-membered, (from 3-membered to 6-membered _{heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10} Each of aryl-C _1-4 alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl) -C _1-4 alkylene is independently unsubstituted or F , Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O—C _1-4 alkylene or R ^d R ^c N—C _{1 —} Substituted with 1, 2, 3 or 4 substituents independently selected from ₄ alkylene;
m is 1 or 2,
X has one of the following subformulae:

Wherein R ⁴ is H or C _1-6 alkyl, and the C _1-6 alkyl may be optionally substituted with 1, 2, 3, or 4 U;
Each R ⁵ , R ⁶ , R ⁷ and R ⁸ is independently H or C _1-6 alkyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached, C _{3 A -8} cycloalkyl group, a 3 to 6 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring, or R ⁷ and R ⁸ are Together with the nitrogen atom to which it is attached, it forms a 3- to 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, C _1-6 alkyl, C _3-8 cycloalkyl, 3 Each of the 6 to 6 membered heterocyclic ring, the C _6-10 aromatic ring or the 5 to 10 membered heteroaromatic ring is independently unsubstituted or 1, 2, 3 , Or 4 U's,
W is a C _3-12 carbocyclic ring or a 3 to 12 membered heterocyclic ring;
Each V and V ′ is independently a C _3-12 cycloalkane ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring;
Each R ^w is independently F, Cl, Br, CN, NO ₂ , oxo (═O), —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR. _{^{c R d, -S (= O}} ) 2 R e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, (R b O) 2 P (═O) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, C _1-6 alkyl, 5 member To 6-membered heteroaryl or 5- to 6-membered heterocyclyl, wherein each of C _1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl is Independently, unsubstituted or substituted with 1, 2, 3, or 4 U;
Each U is independently F, Cl, Br, NO ₂ , CN, oxo (═O), N ₃ , OR ^b , —NR ^c R ^d , C _1-6 alkyl or C _1-6 haloalkyl;
Each s and t is independently 0, 1, 2 or 3,
p is 1, 2 or 3, and each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _{1 -4} alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene Or R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic ring, wherein C _1-6 alkyl, C _{2- 6 alkenyl, C 2-6} alkyl _{Le, C 3-6 cycloalkyl, C 3-6} cycloalkyl _{-C 1-4} alkylene, heterocyclyl from 3-membered to 6-membered, (from 3-membered to 6-membered _{heterocyclyl) -C 1-4} alkylene, _{C 6 -10} aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene and 3 to 6 membered each heterocyclic ring, independently, either unsubstituted, or _{F, Cl, CN, OH,} NH 2, C 1-6 _{alkyl, C 1-6 haloalkyl, C 1-6} alkoxy or _{C 1} Substituted with 1, 2, 3, or 4 substituents independently selected from _-6 alkylamino.

  In other embodiments, the invention provides a compound having Formula (II), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. About.

In the formula, A, R ¹ , R ³ , X, R ′, n and q are as defined in the present specification.

In other embodiments, A is a C _3-12 carbocyclic ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring; And q is 0, 1, 2, 3, 4 or 5.

In other embodiments, each R ¹ and R ³ is independently H, F, Cl, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^{d 1} , OR ^b , —NR ^c R ^d , C _1-3 alkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl, wherein Each of C _1-3 alkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is independently unsubstituted or F, Cl 1, 2, 3 or 4 substituents independently selected from OR ^b , —NR ^c R ^d , C _1-3 alkyl, C _1-3 haloalkyl or R ^b O—C _1-2 alkylene Has been replaced by

In other embodiments, each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 to 6 membered. Heterocyclyl, (5- to 6-membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5- to 6-membered heteroaryl, (5- to 6-membered heteroaryl Aryl) -C _1-2 alkylene or two adjacent R ² together with the atoms to which they are attached are C _5-6 carbocyclic rings, 5- to 6-membered heterocycles Forming a formula ring, a benzene ring or a 5- to 6-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 members 6 members Up to heterocyclyl, (5- to 6-membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5 to 6-membered heteroaryl, (from 5 to 6 member Each of the heteroaryl) -C _1-2 alkylene, C _5-6 carbocyclic ring, 5- to 6-membered heterocyclic ring, benzene ring and 5- to 6-membered heteroaromatic ring Is unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is not F.

In other embodiments, each R ′ is independently F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , —C (═O) R ^a , —C (═O) NR. ^{cR d} , C _1-9 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene or 5 to 6 membered hetero Aryl, wherein C _1-9 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-4 alkylene and 5 to 6 member. Each of the heteroaryl up to is independently unsubstituted or from F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , methyl, ethyl, n-propyl or i-propyl Independently selected Substituted with one, two, three, or four selected substituents.

In other embodiments, each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _{1 -3} haloalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene, or R ^c and R ^d together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring, where methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene and 5 to 6 membered Duplicate Each of the cyclocyclic rings is independently unsubstituted or one independently selected from F, Cl, CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl or methoxy Substituted with 2, 3, or 4 substituents.

  In other embodiments, X has one of the following subformulae:

In the formula, W, V, V ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^w and s are as defined in the present specification.

In other embodiments, W is a C _6-8 carbocyclic ring or a _6-8 membered heterocyclic ring.

In other embodiments, V is a C _3-8 cycloalkane ring, a 3 to 8 membered heterocyclic ring, a benzene ring or a 5 to 6 membered heteroaromatic ring.

In other embodiments, V ′ is a C _3-8 cycloalkane ring, a 3 to 8 membered heterocyclic ring, a benzene ring or a 5 to 6 membered heteroaromatic ring.

In other embodiments, each R ^w is independently F, Cl, Br, CN, NO ₂ , oxo (═O), —C (═O) R ^a , —C (═O) OR ^b , — _{^{C (= O) NR c R}} d, -S (= O) 2 R e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, ( R ^b O) ₂ P (═O) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, methyl, Ethyl, i-propyl, n-propyl, n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyrazolyl, where methyl, ethyl , I-propyl, n-propyl, n-butyl, t-butyl, tetrazo Each of lyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted or 1, 2, 3, or 4 U Has been replaced by

In other embodiments, each U is independently F, Cl, Br, CF ₃ , NO ₂ , CN, oxo (═O), N ₃ , OR ^b , —NR ^c R ^d , methyl, ethyl, i -Propyl, n-propyl, n-butyl or t-butyl.

In other embodiments, A is a C _5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, a benzene ring, a naphthalene ring, or a 5- to 6-membered heteroaromatic ring.

In other embodiments, each R ² is independently F, ethynyl, propynyl, OR ^b , C _3-6 carbocyclyl, 5 to 6 membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, Furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, Isoquinolyl, phenoxytinyl,

Where ethynyl, propynyl, C _3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benz Imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxytinyl,

Each independently is unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is F Absent.

  In other embodiments, X has one of the following subformulae:

In the formula, R ^w , s, and V ′ are as defined herein.

In other embodiments, A is a C _5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole, pyridine, pyrazole, imidazole, benzimidazole, triazole. , Tetrazole, oxazole, oxadiazole, 1,3,5-triazine, thiazole, thiophene, benzothiophene, pyrazine, pyridazine, pyrimidine, indole, purine, quinoline or isoquinoline.

  In other embodiments, the present invention provides compounds having Formula (III), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, R ¹ , R ² , R ³ , m, n and R ^w are as defined in the present specification.

  In other embodiments, the present invention provides compounds having Formula (IV), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, A, R ¹ , R ³ , R ′, n, q and R ^w are as defined in the present specification.

  In other embodiments, the invention provides compounds having Formula (V), or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. About.

In the formula, R ¹ , R ² , R ³ , m, n and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VI), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, A, R ¹ , R ³ , R ′, n, q and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, R ¹ , R ² , R ³ , m, n, s, V ′ and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having Formula (VIII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof About.

In the formula, A, R ¹ , R ³ , R ′, n, q, s, V ′ and R ^w are as defined in the present specification.

  In other embodiments, the invention provides a compound having one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or Although related to prodrugs, the compounds are not limited to these structures.

  In one aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein.

  In certain embodiments, the pharmaceutical compositions provided herein further comprise a pharmaceutically acceptable carrier, adjuvant, vehicle or combination thereof.

  In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents.

  In other embodiments, the therapeutic agent disclosed herein is an anti-influenza virus agent or an anti-influenza virus vaccine.

  In other embodiments, the pharmaceutical composition is in the form of a liquid, solid, semi-solid, gel or spray.

  In other embodiments, a pharmaceutical composition, wherein the therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol, ribavirin, stakifrine, ingavirin, Fludase, CAS number 14222050-75-6, JNJ-872, AL-794, influenza vaccine (FluMist Quadrivent (R), Fluarix (R) Quadrivalent, Fluzone (R) Quadrivent (R), Flucelvax (R) Registered trademark))) or a combination thereof.

  In other aspects, provided herein are compounds or compounds disclosed herein in the manufacture of a medicament for preventing, treating, treating, or alleviating a disorder or disease resulting from a viral infection in a subject. Use of the pharmaceutical composition is provided.

  In certain embodiments, the viral infection disclosed herein is an influenza virus infection.

  In another aspect, provided herein is the use of a compound or pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting an influenza virus RNA polymerase.

  In one embodiment, the salt is a pharmaceutically acceptable salt thereof. The phrase “pharmaceutically acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the mammal to be treated. Say.

  In other embodiments, the salt need not be a pharmaceutically acceptable salt thereof, but for the preparation and / or purification of the compounds of the invention and / or separation of the enantiomers of the compounds of the invention. It may be useful as an intermediate of

  Pharmaceutically acceptable acid addition salts include inorganic or organic acids such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bicarbonate, Sulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophylate, citrate, ethanedisulfonate, fumarate, glucoceptate, gluconate, glucuronate, hippurate , Hydrogen iodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate , Napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalact Emissions, propionate, stearate, succinate, subsalicylate, tartrate, may be generated by tosylate and trifluoroacetate.

  Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

  Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, Includes ethane sulfonic acid, toluene sulfonic acid, sulfosalicylic acid and the like.

  Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases.

  Organic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, and particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

  Organic bases from which salts can be derived include substituted amines including, for example, primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, corrinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

  The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic groups by conventional chemical methods. In general, such salts can be obtained by combining these compounds in free acid form with a stoichiometric amount of a suitable base (eg, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.). It can be prepared by reacting or by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. These reactions are typically carried out in water or in an organic solvent or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred where practicable. A list of additional suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985), and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl. and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

  Furthermore, the compounds disclosed herein (including salts thereof) may be obtained in the form of their hydrates or may contain other solvents used for their crystallization. The compounds of the present invention may form solvates with pharmaceutically acceptable solvents (including water) in essence or intention, and therefore the present invention is solvated forms and unsolvated It is contemplated to include both forms.

Any formula provided herein is intended to represent isotopically enriched and isotopically enriched forms of the compounds. Isotopically enriched compounds have the structure represented by the formulas given herein, except that one or more atoms are replaced with atoms having a selected atomic weight or mass number. Have. Examples of isotopes that can be incorporated into the compounds of the present invention are ² H (deuterium, D), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁸ F, ³¹ P, ³² P, ³⁶ S, ³⁷ Cl, Contains isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, such as ¹²⁵ I.

In other aspects, compounds of the invention include isotopically enriched compounds as defined herein, including those containing radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F, or ² H and Some contain non-radioactive isotopes such as ¹³ C. Such isotopically enriched compounds are positron tomographic methods including metabolic studies (using ¹⁴ C), reaction kinetic studies (eg using ² H or ³ H), drug or substrate biodistribution assays. It is useful in detection or imaging techniques such as (PET) or single photon emission tomography (SPECT), or radiation therapy of affected subjects. In particular, ¹⁸ F-enriched compounds may be particularly preferred in PET or SPECT studies. Isotopically enriched compounds of formula (I) were generally prepared by conventional techniques known to those skilled in the art or using appropriate isotope labeled reagents in place of previously used unlabeled reagents. It can be prepared by methods analogous to those described in the accompanying examples and preparation methods.

Further, substitution with heavy isotopes, particularly deuterium (ie, ² H or D), may have high metabolic stability, eg, increased half-life or reduced required dosage in vivo, or improved therapeutic index, such as May provide certain therapeutic benefits resulting from an improved in vivo half-life or reduced required dosage, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of the compound of formula (I). The enrichment of such heavy isotopes, particularly deuterium, can be defined by the isotope enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a particular isotope. Where a substituent in a compound of the invention is shown to be deuterium, such a compound must have at least 3500 (52.5 for each designated deuterium atom) for each designated deuterium atom. % Deuterium introduction), at least 4000 (60% deuterium introduction), at least 4500 (67.5% deuterium introduction), at least 5000 (75% deuterium introduction), at least 5500 (82.5% Deuterium introduction), at least 6000 (90% deuterium introduction), at least 6333.3 (95% deuterium introduction), at least 6466.7 (97% deuterium introduction), at least 6600 (99% deuterium introduction) Introduction), with an isotopic enrichment factor of at least 6633.3 (99.5% deuterium introduction). Pharmaceutically acceptable solvates according to the invention include those in which the crystalline solvent is isotopically substituted, for example D ₂ O, d ₆ -acetone, DMSO-d ₆ .

Pharmaceutical compositions, preparation and administration of the compounds of the invention The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention or a stereoisomer thereof. In one embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, and optionally other therapeutic and / or prophylactic ingredients. In one embodiment, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

  Pharmaceutically acceptable carriers can include inert ingredients that do not unduly inhibit the biological activity of the compounds described herein. Pharmaceutically acceptable carriers should be biocompatible, ie non-toxic, non-inflammatory, non-immunogenic, and have no other undesired responses when administered to a treated subject. It is. Standard pharmaceutical formulation techniques can be used.

  As noted above, the pharmaceutically acceptable compositions disclosed herein further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, and when used herein, the composition Is any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives suitable for the particular dosage form desired , Solid binders, lubricants and the like. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J. Swarbrick, each of which is incorporated herein by reference. and JC Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in the preparation of pharmaceutically acceptable compositions and known techniques for their production. Any conventional carrier medium may produce an undesirable biological effect, or interact in a deleterious manner with any other component of the pharmaceutically acceptable composition, etc. Except as otherwise noted, its use is contemplated to be within the scope of the present invention.

  Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, serum proteins such as alumina, aluminum stearate, lecithin, human serum albumin, phosphate , Buffer substances such as glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, three Salts or electrolytes such as magnesium silicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, methylcellulose, hydroxypropylmethylcellulose, wool fat, lactose, sugars such as glucose and sucrose, corn Starches such as koshi starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, cocoa butter and excipients such as cocoa butter, peanut oil Oils such as cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol or polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, magnesium hydroxide and hydroxylated Buffers such as aluminum, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solution, and sodium lauryl sulfate and Including other non-toxic compatible lubricants such as magnesium stearate, and colorants, mold release agents, coating agents, sweeteners, fragrances and fragrances, preservatives and antioxidants may also be at the discretion of the formulator. It can be present in the composition.

  Pharmaceutically acceptable compositions are administered orally to humans and other animals, rectally, parenterally, cystically, intravaginally, intraperitoneally based on the severity of the infection being treated. Or topically (by powder, ointment, drops or patches), orally, as an oral or nasal spray or the like.

  Liquid formulations for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may be, for example, water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil Common in the field such as solubilizers and emulsifiers (especially cottonseed, peanut, corn, germ, olive, castor and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof It may contain the inert diluent used. In addition to inert diluents, oral compositions can also include adjuvants such as wetting, emulsifying or suspending agents, sweetening, flavoring and perfuming agents.

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.A. S. P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  Injectable formulations can be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. .

  In order to prolong the effect of the compounds or compositions described herein, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with low water solubility. The drug absorption rate then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration specifically comprise a compound described herein that is solid at room temperature but liquid at body temperature, and therefore melts in the rectum or vaginal cavity to produce the active compound. Suppositories that can be prepared by mixing with a suitable nonirritating excipient or carrier, such as cocoa butter to be released, polyethylene glycol or suppository wax.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is combined with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or calcium phosphate and / or (a) a filler or swelling agent such as starch, Lactose, sucrose, glucose, mannitol and silicic acid, (b) adhesives such as carboxymethylcellulose, alginate, gelatin, polyethylene pyrrole ketone, sucrose and gum arabic, (c) humectants such as glycerol, (d) disintegrants, Eg agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) blocker solutions such as paraffin, (f) absorption enhancers such as quaternary ammonium compounds, (g) wet Agents such as cetyl Alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite, (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer.

  Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose or lactose, and excipients such as high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. These may optionally include an opacifier, which may be a composition that releases the active ingredient alone, or preferentially, at a specific site in the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose or lactose and excipients such as high molecular weight polyethylene glycols.

  The active compound can also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms also contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is customary. obtain. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. These may optionally include an opacifier, which may be a composition alone or preferentially releasing the active ingredient, optionally in a delayed manner, at specific sites in the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches with the added benefit of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or implanted reservoir. Can be administered via The term “parenteral” as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and cranial. Includes internal injection or infusion techniques. Specifically, the composition is administered orally, intraperitoneally or intravenously. Specifically, the composition is administered orally, intraperitoneally or intravenously. Specifically, the composition is administered orally, intraperitoneally or intravenously.

  Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions can be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and natural pharmaceutically acceptable oils such as olive oil or castor oil are also particularly useful in their polyoxyethylated ones. It is. These oily solutions or suspensions are also similar dispersions commonly used in formulations of pharmaceutically acceptable dosage forms including long chain alcohol diluents or dispersants such as carboxymethylcellulose, or emulsions and suspensions. Agents can be included. Formulation of other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms Can also be used for these purposes.

  The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include but are not limited to lactose and corn starch. A lubricant such as magnesium stearate is also typically added. Diluents useful in oral administration in capsule form include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added.

  Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These should be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will dissolve in the rectum to release the drug. Can do. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

  The pharmaceutical compositions described herein can also be administered topically, especially when the target of treatment includes areas or organs that are readily accessible by topical application involving diseases of the eye, skin, or lower intestinal tract. . Appropriate topical formulations are readily prepared for each of these areas or organs.

  Topical application of the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used.

  For topical application, the pharmaceutical compositions may be prepared in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be prepared in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

  For ophthalmic use, the pharmaceutical composition is an isotonic pH as a finely divided suspension in isotonic pH adjusted sterile saline or specifically with or without a preservative such as benzylalkonium chloride. It can be formulated as a solution in conditioned sterile saline. Alternatively, for ophthalmic use, the pharmaceutical composition can be prepared in an ointment such as petrolatum.

  The pharmaceutical composition can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional Can be prepared as a solution in saline using any of the solubilizers or dispersants.

  The compounds for use in the methods of the invention can be prepared in unit dosage form. The term “unit dosage form” refers to a physically discrete unit suitable as a unit dose for the subject to be treated, each unit optionally combined with a suitable pharmaceutical carrier to produce the desired therapeutic effect. Contains a predetermined amount of active substance calculated to occur. The unit dosage form can be one of a once daily dose or multiple daily doses (eg, about 1 to 4 times per day or more). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

Use of Compounds and Pharmaceutical Compositions The compounds and pharmaceutical compositions provided herein are used in the manufacture of a medicament for preventing, treating or alleviating a disorder or disease caused by a viral infection in a diseased body. obtain. In some embodiments, the viral infection is an influenza virus infection.

  Also provided herein is the use of the above compounds and pharmaceutical compositions in the manufacture of a medicament that is an inhibitor of influenza virus RNA polymerase.

  Provided herein are methods for treating, preventing or delaying an infection caused by a virus, wherein the method requires a therapeutically effective amount of a compound or pharmaceutical composition described herein in need of treatment. Administration to a afflicted subject. Here, the virus is an influenza virus. Further, the compound or pharmaceutical composition thereof can be co-administered with other therapies or therapeutic agents. Co-administration can occur simultaneously, sequentially, or at specific time intervals.

  The dose of compound or pharmaceutical composition required to perform a function such as treatment, prevention or delay is usually determined by the particular compound being administered, the subject, the particular disease or disorder and its severity, the route of administration and Depending on the frequency, etc., it must be determined by the attending physician according to specific conditions. For example, when a compound or pharmaceutical composition of the invention is administered intravenously, administration can be once a week or at longer intervals.

  As noted above, the present invention provides a new class of compounds that can be used as inhibitors of influenza virus RNA polymerase. The compounds of the present invention are suitable for preparing medicaments as various dosage forms, which can be used to treat seasonal influenza, avian influenza, swine influenza and Tamiflu resistant influenza virus variants.

  In addition to being useful for human treatment, these compounds are also useful for veterinary treatment of animals such as companion animals, exotic animals and livestock animals. In other embodiments, the animals disclosed herein include horses, dogs and cats. As used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof.

General Synthetic Procedures For purposes of illustrating the invention, the following practices are listed. It should be understood that the present invention is not limited to these examples and that the present invention provides only a method for practicing the present invention.

  In general, the compounds disclosed herein can be prepared by the methods described herein, where the substituents are as defined for formula (I), unless otherwise specified. The following several non-limiting schemes and examples are presented to further illustrate the present invention.

  One skilled in the art will recognize that the described chemical reactions can be readily adapted to prepare many other compounds disclosed herein, and for preparing the compounds disclosed herein. It will be appreciated that alternative methods are considered within the scope disclosed herein. For example, the synthesis of unillustrated compounds in accordance with the present invention can be performed by other suitable methods known in the art other than those described, with modifications obvious to those skilled in the art, for example, by appropriate protection of interfering groups. It can be successfully achieved by utilizing reagents and / or by making changes beyond the values of the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to prepare other compounds disclosed herein.

  In each example described below, all temperatures are set forth in degrees Celsius unless otherwise noted. Reagents were purchased from commercial sources such as Aldrich Chemical Company, Arco Chemical Company, Alfa Chemical Company and J & K Scientific Ltd. and were used without further purification unless otherwise specified. Common solvents are Shantou XiLong Chemical Factory, Guangzhou Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Tianjing Fuchen Chemical Reagent Factory, Wuhan XinHuayuan technology development co., LTD., Qingdao Purchased from commercial sources such as Tenglong Reagent Chemical Ltd., Qingdao Ocean Chemical Factory, Beijin Ouhe Technology Co., Ltd., Shanghai Topbiochem Technology Co., Ltd and Accela ChemBio Co., Ltd.

The solvent was refluxed with sodium to give anhydrous THF, 1,4-dioxane, toluene, and ether. The solvent was refluxed with calcium hydride to give anhydrous CH ₂ Cl ₂ and CHCl ₃ . EtOAc, PE, n-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were treated with anhydrous Na ₂ SO ₄ before use.

  The reactions shown below are generally performed under a positive pressure of nitrogen or argon, or in a dry tube (unless otherwise specified) in an anhydrous solvent, and the reaction flask is typically introduced with a substrate and reagents via a syringe. A rubber septum was attached. Glassware was oven dried and / or heat dried.

  Column chromatography was performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

¹ H NMR spectra using CDCl ₃ , d ₆ -DMSO, CD ₆ OD or d ₆ -acetone (reported in ppm) as solvent and TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. And recorded at rt on a Bruker 400 MHz or 600 MHz spectrometer. When peak multiplicity was reported, the following abbreviations were used: s (single line), d (double line), t (triple line), m (multiple line), br (widening), dd (two Double line of double line), and dt (double line of triple line). Coupling constants are reported in hertz (Hz) when given.

Low-resolution mass spectral (MS) data was measured on an Agilent 6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent Zorbax SB-C18 column (2.1 × 30 mm, 3.5 μm). The flow rate is 0.6 mL / min and the mobile phase is in gradient mode (5% -95%) between A (0.1% formic acid in CH ₃ CN) and B (0.1% formic acid in H ₂ O). Combining, using an ESI source, the HPLC peak was recorded at 210/254 nm with UV-Vis detection.

  Purification of the compound by preparative chromatography was performed using Agilent 1260 series high performance liquid chromatography (Pre-HPLC) or CalesePump 250 Series high performance liquid chromatography (Pre-HPLC) with UV detection at 210/254 nm (column: NOVASEP, 50 / 80mm, DAC).

The following abbreviations are used throughout this specification:
_{ACOH, HAc, HOAc, CH 3} COOH acid _ACOK, KOAc, CH 3 COOK potassium acetate BnOH phenyl carbinol _Bu 4 NF and tetrabutylammonium fluoride BOC, Boc tert-butoxycarbonyl _(Boc) 2 O di -tert- butyl n-BuOH n-butyl alcohol CHCl ₃ chloroform CDC1 ₃ chloroform-d
CD ₃ OD methyl alcohol-d ₄
DCM, CH ₂ Cl ₂ dichloromethane CH ₃ CN, MeCN acetonitrile CH ₃ Cl chloromethane CH ₃ I iodomethane CH ₃ SO ₂ Cl, MsCl methylsulfonyl chloride Cbz benzyloxycarbonyl CL clearance DIEA, DIPEA, iPr ₂ Net N, N-diisopropyl Ethylamine DMF N, N-dimethylformamide, dimethylformamide DMF-DMA N, N-dimethylformamide dimethyl acetal DME dimethyl ether DMAP 4-dimethylaminopyridine DMSO dimethyl sulfoxide DMSO-d ₆ dimethyl sulfoxide-d ₆ , deuterated DMSO
DPPA Diphenylphosphoryl azide EA, EtOAc Ethyl acetate Et ₃ N, TEA Triethylamine Et ₂ O Diethyl ether EtOH Ethyl alcohol EC ₅₀ 50% Effective concentration g Gram wt Weight fraction h Time H ₂ Hydrogen H ₂ O Water HCl Hydrogen chloride H ₂ O ₂ Hydrogen peroxide H ₃ PO ₄ Phosphate H ₂ SO ₄ Sulfate HNO ₃ Nitric acid HCOK Potassium formate HCOONH ₄ Ammonium formate HPLC High performance liquid chromatography HPTLC High performance thin layer chromatography HRMS High resolution mass spectrometry I ₂ Iodine Fe Iron MgSO ₄ Sulfate Magnesium CH ₃ OH, MeOH Methanol MeI, CH ₃ I iodomethane mL, ml milliliter min min N ₂ nitrogen
NH ₃ ammonia NMP N-methylpyrrolidone NaHCO ₃ sodium bicarbonate NaBH ₄ sodium borohydride NaBH ₃ CN sodium cyanoborohydride NaOMe, NaOCH ₃ , CH ₃ ONa sodium methoxide NaOH sodium hydroxide NaCl sodium chloride NaH ₂ PO ₄ phosphorus disodium hydrogen sodium NaH sodium hydride NaI sodium iodide _Na 2 SO ₄ sulfate _Na 2 _S 2 _{O 3} sodium thiosulfate NBS N-bromosuccinimide NIS N-iodosuccinimide NCS N-chlorosuccinimide _NH 4 Cl ammonium chloride NH ₂ OH · HCl Hydroxylamine hydrochloride psi Pounds per square inch Pd / C Palladium Pd (OAc) on activated carbon ₂ Palladium diacetate Pd (OH ) ₂ palladium hydroxide Pd _{(PPh 3) 4} tetrakis (triphenylphosphine) palladium Pd _{(PPh 3)} 2 Cl ₂ bis (triphenylphosphine) palladium (II) chloride _{Pd (dppf) Cl 2, PdCl} 2 (dppf) [ 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II)
Pd (dppf) Cl ₂ .CH ₂ Cl ₂ 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane adduct Pd (dtbpf) Cl ₂ [1,1′-bis (di-tert- Butylphosphino) ferrocene] dichloropalladium (II)
Pd ₂ (dba) ₃ tris (dibenzylideneacetone) dipalladium P (t-Bu) ₃ tri-tert-butylphosphine PE Petroleum ether (60-90 ° C.)
POCl ₃ Phosphorus oxychloride K ₂ CO ₃ Potassium carbonate K ₃ PO ₄ Potassium phosphate KOH Potassium hydroxide RT, rt, r.p. t. Room temperature Rt retention time SOCl ₂ thionyl SI therapeutic index t-BuOK potassium tert- butoxide THF tetrahydrofuran TFA trifluoroacetic acid TBAI tetrabutylammonium iodide TBS tris (hydroxymethyl) chloride aminomethane salt buffer TsCl distribution of tosyl chloride Ts tosyl Vss Apparent Volume XPhos 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-tri-i-propyl-1,1′-biphenylZn μl microliter The following scheme lists the steps for synthesizing the compounds of the present invention. Wherein R ¹ , R ² , R ³ , R ^w , R ′, n, q, s, V ′ and A are as defined herein, and R ^h is H or F. , R ^g is OH or Cl.

  Scheme 1

Intermediates having formula (6) can be prepared by the process shown in Scheme 1. First, compound (1) is reacted with a brominating reagent (eg, bromine, NBS, etc.) at rt in a polar solvent (eg, N, N-dimethylformamide) or a medium polarity solvent (eg, dichloromethane) (2) may be given. Compound (2) can react with p-tosyl chloride (3) to give compound (4). Compound (4) can react with compound (5) in the presence of a palladium catalyst (eg, Pd (dppf) Cl ₂ , Pd (PPh ₃ ) _4, etc.) to give intermediate (6).

  Scheme 2

  Compounds having formula (17) can be prepared by the process shown in Scheme 2. Initially, compound (7) can react with compound (8) in the absence of light to give compound (9). Compound (9) can give compound (10) through a ring-opening reaction in the presence of a base (for example, sodium methoxide and the like). Compound (10) can then react with DPPA and phenyl carbinol (11) to give compound (12) via a rearrangement reaction under alkaline conditions. The amino protecting group of compound (12) can be removed under reducing conditions to give compound (13). The coupling reaction between compound (13) and compound (14) can occur under alkaline conditions to give compound (15). In the presence of a palladium catalyst, a Suzuki cross coupling reaction between compound (15) and compound (6) can occur to give compound (16). Finally, the protecting group of compound (16) can be removed in the presence of a base to give compound (17).

  Scheme 3

  Compounds having formula (24) can be prepared by the process shown in Scheme 3. Initially, compound (18) may react with urea (19) under heating conditions to give compound (20). Compound (20) can give compound (21) through a chlorination reaction in the presence of phosphorus oxychloride. Compound (21) can then react with compound (13) under alkaline conditions to give compound (22). In the presence of a palladium catalyst, a Suzuki cross coupling reaction can occur between compound (22) and compound (6) to give compound (23). Finally, the protecting group of compound (23) can be removed in the presence of a base to give compound (24).

  Scheme 4

  Compounds having formula (30) can be prepared by the process shown in Scheme 4. Initially, a Suzuki cross coupling reaction can occur between compound (25) and boric acid compound (26) to give compound (27). Compound (27) can then react with compound (13) under alkaline conditions to give compound (28). In the presence of a palladium catalyst, a Suzuki cross coupling reaction can occur between compound (28) and compound (6) to give compound (29). Finally, the protecting group of compound (29) can be removed in the presence of a base to give compound (30).

  Scheme 5

  Compounds having formula (36) can be prepared by the process shown in Scheme 5. Initially, compound (31) can react with compound (13) under alkaline conditions to give compound (32). Compound (32) and boric acid compound (33) can then give compound (34) via a Suzuki cross coupling reaction. In the presence of a palladium catalyst, a Suzuki cross coupling reaction occurs between compound (34) and compound (6) to give compound (35). Finally, the protecting group of compound (35) can be removed in the presence of a base to give compound (36).

  Scheme 6

  Compounds having formula (43) can be prepared by the process shown in Scheme 6. Initially, compound (37) may react with compound (38) to give compound (39). Compound (39) and compound (40) can then give compound (41) via a condensation reaction. A Suzuki cross coupling reaction can occur between compound (41) and compound (6) in the presence of a palladium catalyst to give compound (42). Finally, the protecting group of compound (42) can be removed in the presence of a base to give compound (43).

  Scheme 7

  Compounds having formula (53) can be prepared by the process shown in Scheme 7. Initially, compound (44) can react with DPPA and compound (11) under alkaline conditions to give compound (45). Compound (45) can then undergo a reduction reaction to give compound (46) under certain conditions (eg, in the presence of a Pd / C catalyst and in a hydrogen atmosphere). Compound (46) can react with compound (47) under alkaline conditions to give compound (48). The amino protecting group of compound (48) can then be removed under acidic conditions to give compound (49). Compound (49) and compound (50) can give compound (51) through a condensation reaction. In the presence of a palladium catalyst, a Suzuki cross coupling reaction can occur between compound (51) and compound (6) to give compound (52). Finally, the protecting group of compound (52) can be removed under alkaline conditions to give compound (53).

DESCRIPTION OF PREFERRED EMBODIMENTS The following examples are used to illustrate the present invention, but should not be construed as limiting the scope of the invention.

Preparation Examples The preparation of the compounds of the invention is described in detail in the following examples, using some of the compounds of the invention as examples.

  Example 1: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) bicyclo [2. 2.2] octane-2-carboxylic acid

Step 1: Meso-endo-tetrahydro-4,7-ethanoisobenzofuran-1,3-dione Maleic anhydride (100 g, 1.02 mol) and chloroform (1000.0 mL) were added sequentially to a 2000 mL dry flask. After that, the mixture was cooled to 0 ° C. and 1,3-cyclohexadiene (112.5 mL, 1.12 mol) was added dropwise. After the addition, the mixture was heated to rt and stirred overnight in the absence of light. After the reaction was complete, the mixture was concentrated in vacuo to remove the solvent. Methanol (700.0 mL) was added to the residue, and the resulting mixture was heated to 50 ° C. and stirred for 10 min, then cooled to 0 ° C. and stirred for 30 min. The mixture was filtered and the filter cake was dried in vacuo at 45 ° C. to give the title compound as a white solid (147 g, 81%).
MS (ESI, pos.ion) m / z: 179.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 6.28 (dd, J = 4.2, 3.4 Hz, 2H), 3.29 (s, 2H), 3.04 (s, 2H), 1.61 (d, J = 7.9 Hz, 2H), 1.22 (d, J = 7.6 Hz, 2H).

Step 2: (+/−)-trans-3- (methoxycarbonyl) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid In a dried flask, meso-endo-tetrahydro-4,7- Ethanoisobenzofuran-1,3-dione (33.50 g, 188.01 mmol) was added and then a solution of sodium methoxide in methanol (5M, 300.8 mL) was added dropwise at 0 ° C. After the addition, the mixture was heated to rt, stirred for 4 days, and then concentrated in vacuo to remove a portion of methanol (about 120 mL). The residue was slowly added to a 0 ° C. aqueous hydrochloric acid solution (277 mL, 18% wt), and a white solid precipitated. The mixture was concentrated in vacuo to remove methanol and the residue was stirred at 0 ° C. for 30 min and then filtered with suction. The filter cake was washed 3 times with water and dried in vacuo to give the title compound as a white solid (37.19 g, 94%).
MS (ESI, neg.ion) m / z: 209.0 [M−H] ⁻ ;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1 H), 6.34 (s, 1 H), 6.17 (s, 1 H), 3.65 (s, 3 H ), 2.94 (s, 1H), 2.91 (d, J = 4.4 Hz, 1H), 2.86 (d, J = 2.4 Hz, 1H), 2.72 (s, 1H), 1.48-1.58 (m, 1H), 1.34-1.44 (m, 1H), 1.26-1.16 (m, 1H), 1.09-0.99 (m, 1H) ).

Step 3: (+/-)-trans-3-(((benzyloxy) carbonyl) amino) bicyclo [2.2.2] octa-5-ene-2-carboxylate (+ in toluene (50 mL) A solution of /-)-trans-3-(methoxycarbonyl)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (6.0 g, 29 mmol) was degassed and filled with nitrogen three times. Afterwards, diphenyl phosphate azide (7.0 mL, 32 mmol) and triethylamine (4.0 mL, 29 mmol) were added in order with a syringe. The mixture was heated to 90 ° C. and stirred for 2 hours, after which phenyl carbinol (3.0 mL, 29 mmol) was added dropwise with a syringe. The mixture was stirred for an additional 3 days while maintaining this temperature. The reaction mixture was cooled to rt and ethyl acetate (60 mL) was added to dilute the mixture. The resulting mixture was washed sequentially with saturated aqueous sodium bicarbonate (60 mL × 2) and saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a yellow oil (8.25 g, 92%).
MS (ESI, pos.ion) m / z: 316.1 [M + H] ^< +>.

Step 4: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in an autoclave was added 3-(((benzyloxy) carbonyl) amino) bicyclo [2.2. 2] Octa-5-ene-2-carboxylic acid (+/-)-trans-methyl (8.21 g, 26.0 mmol), tetrahydrofuran (20 mL) and methanol (20 mL) were added in order. To the solution was added Pd / C (10% wt Pd, 1.40 g) and the mixture was stirred overnight at rt under 2.76 bar hydrogen pressure. After filtering the reaction mixture through a celite pad to remove the catalyst, the filter cake was washed sequentially with methanol (20 mL) and ethyl acetate (20 mL). The combined filtrates were concentrated in vacuo to give a colorless oil which was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20/1 to 10/1) to give the title compound as a colorless oil. (3.95 g, 83%).
MS (ESI, pos.ion) m / z: 184.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.68 (s, 3H), 3.31 (d, J = 6.7 Hz, 1H), 2.11 (d, J = 6.7 Hz, 1H), 1.98-1.91 (m, 1H), 1.83-1.71 (m, 1H), 1.60-1.33 (m, 10H).

Step 5: 3-((2-Chloroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl in THF (20 mL) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (1.83 g, 9.99 mmol), 2,4-dichloroquinazoline (2.5 g, 15 mmol) and DIPEA (8 .7 mL, 50 mmol) was added. The mixture was stirred at rt overnight. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a white solid (3.13 g, 95%).
MS (ESI, pos.ion) m / z: 356.8 [M + H] ^< +>.

Step 6: 3-Bromo-5-fluoro-1H-pyrrolo [2,3-b] pyridine 5-fluoro-1H-pyrrolo [2,3-b] pyridine (1 g, 7.34 mmol) in DMF (10 mL) To the solution was added bromine (0.75 mL, 14.5 mmol). The mixture was stirred at rt for 4 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow powder (0.6 g, 40%). .
MS (ESI, pos.ion) m / z: 216.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.23 (s, 1H), 8.35-8.21 (m, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 8.9, 2.6 Hz, 1H).

Step 7: 3-Bromo-5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine 3-Bromo-5-fluoro-1H-pyrrolo [2,3-b] in THF (5 mL) To a solution of pyridine (0.74 g, 2.0 mmol) was added NaH (127 mg, 3.0 mmol) at 0 ° C. and the mixture was stirred for 30 min while maintaining this temperature before TsCl (458 mg, 2.4 mmol). Was added. The resulting mixture was heated to rt and stirred overnight. The reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow solid (740 mg, 90%).
MS (ESI, pos.ion) m / z: 370.8 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.32 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.84 (s, 1H), 7.47 (Dd, J = 7.8, 2.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 2.38 (s, 3H).

Step 8: 5-Fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine DME (5 mL) was added 3-bromo-5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine (175 mg, 0.22 mmol), Pd (dppf) Cl ₂ (70 mg, 0.09 mmol) and KOAc (144 mg, 0.47 mmol) was added. After removing air in the mixture by bubbling with nitrogen for 10 min, bis (pinacolato) diboron (190 mg, 0.71 mmol) was added to the mixture. The mixture in the tube was sealed and stirred at 105 ° C. for 2 h under microwave conditions. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (20 mL). The mixture was then filtered through a pad of celite and the filter cake was washed with ethyl acetate (20 mL × 2). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow solid (130 mg, 65.9). %).
MS (ESI, pos.ion) m / z: 417.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.27 (d, J = 1.2 Hz, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.89 (dd, J = 8.5, 2.7 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 2.39 (s, 3H), 1 .37 (s, 12H).

Step 9: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) bicyclo [2.2.2] To a mixed solvent of octane-2-carboxylic acid (+/−)-trans-methyl 2-methyltetrahydrofuran (8 mL) and water (1 mL), 5-fluoro-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (305 mg, 0.73 mmol), K ₃ PO ₄ (276 mg, 1.31 mmol), Pd _{2 (dba) 3 (46mg, 0.1mmol} ), 3 - ((2- chloroquinazoline-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (150mg, 0.43mmo ) And XPhos (23mg, 0.1mmol) was added. Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture in the sealed tube was stirred at 110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (20 mL) and then filtered through a celite pad. After the filtrate was partitioned and the organic layer was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a white solid (255 mg 97%).
MS (ESI, pos.ion) m / z: 600.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.86 (dd, J = 9.0, 2.8 Hz, 1H), 8.78 (s, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 15.8, 7 .6 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 8.9 Hz, 3H), 5.87 (d, J = 6.3 Hz, 1H) 4.98 (s, 1H), 3.76 (s, 3H), 2.39 (s, 3H), 2.16-2.08 (m, 2H), 1.81-1.69 (m , 6H), 1.29-1.24 (m, 2H).

Step 10: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] in THF / MeOH (v / v = 1/1, 8 mL)) ] Pyridin-3-yl) quinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (150 mg, 0.25 mmol) in water Aqueous sodium oxide (4M, 0.2 mL, 0.8 mmol) was added. The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to pH about 6.0, and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (80 mg, 74%).
MS (ESI, pos.ion) m / z: 432.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 432.1831 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 432.1836;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.18 (s, 1H), 9.49 (s, 1H), 8.92 (s, 1H), 8.63 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.69 (s, 1H), 5.19 (s, 1H), 3.16 (s, 1H), 2.14 (s, 1H), 2.06 (s, 1H), 1.85 (s , 3H), 1.57 (m, 6H).

  Example 2: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazoline- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5,6,7,8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl THF (15 mL) to 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (0.68 g, 3.69 mmol), 2,4-dichloro-5 , 6,7,8-tetrahydroquinazoline (1.13 g, 2.46 mmol) and DIPEA (4.5 mL, 24.6 mmol) were added. The mixture was stirred at 65 ° C. overnight. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a white solid (862 mg, 17%).
MS (ESI, pos.ion) m / z: 350.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.75 (d, J = 5.1 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 3.77 (s, 3H), 2.68 (t, J = 5.9 Hz, 2H), 2.35 (d, J = 5.7 Hz, 1H), 2.29-2.23 (m, 2H), 2.05 ( s, 1H), 1.96 (d, J = 2.5 Hz, 1H), 1.89-1.76 (m, 6H), 1.67-1.54 (m, 5H), 1.26 ( d, J = 7.1 Hz, 1H).

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazolin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl In a mixed solvent of 2-methyltetrahydrofuran (8 mL) and water (1 mL), 5-fluoro-3- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (251 mg, 0.59 mmol), K ₃ PO ₄ (253 mg, 1.18 mmol), Pd ₂ (dba) ₃ (83 mg, 0.1 mmol), 3-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl) amino) bicyclo [2 2.2 Octane-2-carboxylic acid (+/-) - trans - was added methyl (150 mg, 0.43 mmol) and XPhos (43 mg, 0.1 mmol). Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture in the sealed tube was stirred at 110 ° C. for 3 hours. The mixture was diluted with ethyl acetate (20 mL) and the resulting mixture was filtered through a celite pad. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a white solid (245 mg, 98%).
MS (ESI, pos.ion) m / z: 605.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.66 (dd, J = 9.0, 2.8 Hz, 1H), 8.61 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.28 (s, 3H), 3.71 (s, 3H), 2.78 (t, J = 5.6 Hz, 2H), 2.39 (d, J = 3. 2 Hz, 4H), 2.06 (s, 1H), 2.01 (s, 1H), 1.89 (d, J = 5.6 Hz, 5H), 1.76-1.67 (m, 5H) 1.37 (s, 3H), 1.27 (d, J = 6.0 Hz, 3H).

Step 3: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazolin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid (+/−)-trans-methyl 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3- b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl ( To a solution of 295 mg, 0.49 mmol) was added a solution of hydrogen chloride in 1,4-dioxane (4M, 0.3 mL, 1.2 mmol). The mixture was stirred at 65 ° C. for 6.5 hours and then diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 2/1) to give the title compound as a white solid (143 mg, 65%).
MS (ESI, pos.ion) m / z: 450.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 10.58 (s, 1H), 8.70 (dd, J = 9.4, 2.6 Hz, 1H), 8.36 (s, 1H) 8.23 (s, 1H), 4.81 (t, J = 5.7 Hz, 1H), 4.66 (d, J = 6.6 Hz, 1H), 3.64 (s, 3H), 2 .81 (d, J = 5.6 Hz, 2H), 2.41 (d, J = 5.7 Hz, 1H), 2.35 (d, J = 6.0 Hz, 2H), 2.05 (s, 2H), 1.88 (d, J = 5.2 Hz, 5H), 1.73-1.49 (m, 7H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazoline- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1H-pyrrolo) in THF / MeOH (v / v = 1/1, 8 mL) [2,3-b] pyridin-3-yl) -5,6,7,8-tetrahydroquinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -To a solution of trans-methyl (105 mg, 0.27 mmol) was added aqueous sodium hydroxide (4 M, 0.6 mL, 2.4 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to pH about 6.0 and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (105 mg, 88%).
MS (ESI, pos.ion) m / z: 436.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 436.2143 [M + H] ⁺ , (C ₂₄ H ₂₆ FN ₅ O ₂ ) [M + H] ⁺ Theoretical: 436.2149;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.35 (s, 1H), 8.57 (dd, J = 9.7, 2.6 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 6.68 (s, 1H), 4.78 (s, 1H), 2.97 (d, J = 6.4 Hz, 1H), 2.68 (s) , 2H), 2.51 (s, 3H), 2.41 (s, 1H), 2.00 (s, 1H), 1.92 (s, 1H), 1.77 (s, 6H), 1 .33 (d, J = 7.2 Hz, 2H), 1.21 (s, 2H).

  Example 3: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (4-methoxyphenyl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (5.5 mL, 48 mmol) in THF (70 mL) was added palladium acetate (0.147 g, 0.64 mmol), triphenylphosphine (0.353 g, 1.28 mmol), 4-methoxybenzeneboronic acid (5 g, 31.9 mmol) and aqueous sodium carbonate (1M, 64 mL, 64 mmol) were added. The mixture was stirred at 60 ° C. for 6 h. After the reaction was complete, the mixture was cooled to rt and concentrated in vacuo to remove the solvent. To the residue was added H ₂ O (100 mL) and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (5.58 g, 68%).
MS (ESI, pos.ion) m / z: 255.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.07 (dd, J = 9.4, 2.4 Hz, 2H), 7.60 (s, 1H), 7.08-6.99 ( m, 2H), 3.91 (s, 3H).

Step 2: 3-((2-Chloro-6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 2,4-Dichloro-6- (4-methoxyphenyl) pyrimidine (1 g, 3.92 mmol) and 3-aminobicyclo [2.2.2] octane-2-carboxylic acid in N, N-dimethylformamide (20 mL) To a solution of acid (+/−)-trans-methyl (1 g, 5.88 mmol) was added potassium carbonate (0.813 g, 5.88 mmol). The mixture was stirred at 50 ° C. overnight. After the reaction was complete, the mixture was diluted with H ₂ O (70 mL) and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 20/1 to 5/1) to give the title compound as a white solid (1.01 g, 64%).
MS (ESI, pos.ion) m / z: 402.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.98 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.72 (s, 1H), 5.46 (d, J = 6.3 Hz, 1H), 4.32 (s, 1H), 3.88 (s, 4H), 3.74 (s, 3H), 2.39 (d , J = 5.1 Hz, 1H), 2.08 (s, 1H), 1.90-1.84 (m, 1H), 1.78-1.71 (m, 2H), 1.70-1. .63 (m, 4H), 1.58 (d, J = 10.2 Hz, 2H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl Into a microwave tube, add 3-((2-chloro-6- (4-methoxyphenyl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (550 mg, 1.368 mmol), 5-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (630 mg, 1.513 mmol), potassium carbonate (380 mg, 2.75 mmol), Pd ( d ppf) Cl ₂ (120 mg, 0.147 mmol), 1,4-dioxane (15 mL) and H ₂ O (0.5 mL) were added. Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture in the microwave tube was stirred at 110 ° C. while causing a 2 h microwave reaction. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate. The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 15/1) to give the title compound as a yellow solid (816 mg, 91 %).
MS (ESI, pos.ion) m / z: 656.2 [M + H] ⁺ ;
¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.70 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 8.11 (S, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.29 (s, 1H), 7.28 (s, 1H), 7.06 (s, 1H) 7.04 (s, 1H), 6.68 (s, 1H), 5.25 (s, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 2.45 ( d, J = 5.3 Hz, 1H), 2.38 (s, 3H), 1.98 (s, 1H), 1.84 (d, J = 11.8 Hz, 2H), 1.75-1. 65 (m, 6H), 1.62-1.53 (m, 2H).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2 2.2] Octane-2-carboxylic acid (+/−)-trans-methyl 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2]) in 1,4-dioxane (10 mL). , 3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans- To a solution of methyl (816 mg, 1.244 mmol) was added a solution of hydrogen chloride in dioxane (4M, 10 mL, 40 mmol). The mixture was stirred at 65 ° C. overnight. After the reaction was complete, the mixture was diluted with ethyl acetate (20 mL) and the resulting mixture was washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a brown solid (350 mg, 56%).
MS (ESI, pos.ion) m / z: 502.2 [M + H] ^< +>.

Step 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidine-4 - yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid MeOH (5mL), THF (5mL ) and _H 2 O in the mixed solvent (5mL) 3 - ((2- (5- fluoro -1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ To a solution of / −)-trans-methyl (350 mg, 0.69 mmol) was added sodium hydroxide (280 mg, 7.00 mmol). The mixture was stirred at rt overnight. After the reaction was complete, the mixture was diluted with 2-methyltetrahydrofuran (20 mL) and the mixture was adjusted to pH 6.0 with dilute hydrochloric acid (1M). The resulting mixture was extracted with 2-methyltetrahydrofuran (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 1/1) to give the title compound as a pale yellow solid (270 mg, 79%).
MS (ESI, pos.ion) m / z: 476.4 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.78 (dd, J = 9.5, 2.5 Hz, 1H), 8.40 (s, 1H), 8.17 (s, 1H) ), 8.04 (s, 1H), 8.02 (s, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 3.89 (S, 3H), 2.56 (d, J = 5.9 Hz, 1H), 2.09 (s, 1H), 2.03 (s, 1H), 1.91 (d, J = 11.4 Hz) , 2H), 1.80-1.70 (m, 4H), 1.57 (s, 1H), 1.54 (s, 1H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.05, 163.07, 162.34, 161.21, 156.85, 155.26, 146.46, 131.73, 131. 53, 130.62, 128.21, 119.09, 119.03, 115.16, 114.56, 114.33, 60.24, 55.72, 28.80, 28.57, 26.02, 24.17, 21.38, 19.42, 14.53.

  Example 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6-phenylpyrimidine To a solution of 2,4,6-trichloropyrimidine (0.29 mL, 2.5 mmol) in THF (5 mL), palladium acetate (8 mg, 0.035 mmol), Triphenylphosphine (18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate (1M, 3.3 mL, 3.3 mmol) were added. The mixture was stirred at 60 ° C. for 6 h under nitrogen protection. After the reaction was complete, the mixture was cooled to rt and concentrated in vacuo to remove the organic solvent. To the residue was added H ₂ O (10 mL) and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 61%).
MS (ESI, pos.ion) m / z: 225.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H), 7.63-7.50 (m, 3H).

Step 2: 3-((2-Chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl N, N-dimethyl 2,4-Dichloro-6-phenylpyrimidine (1.52 g, 6.7 mmol) and 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (±) -trans-methyl in formamide (10 mL) To a solution of (1.84 g, 10.0 mmol), potassium carbonate (0.92 g, 6.7 mmol) was added. The mixture was stirred at rt overnight. After the reaction was complete, the mixture was diluted with H ₂ O (50 mL) and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 20 / 1-10 / 1) to give the title compound as a white solid (1.65 g, 66%).
MS (ESI, pos.ion) m / z: 372.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.04-7.91 (m, 2H), 7.51-7.41 (m, 3H), 6.78 (s, 1H), 5 .41 (s, 1H), 4.32 (s, 1H), 3.73 (s, 3H), 2.38 (d, J = 5.1 Hz, 1H), 2.07 (s, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.70-1.60 (m, 4H), 1.57 (m, 2H), 1.51-1.41 (m, 1H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl Into a microwave tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (240 mg, 0.57 mmol), 3-((2-chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2 .2.2] octane-2-carboxylic acid (+/-) - trans - methyl (220 mg, 0.59 mmol), potassium carbonate _{(160mg, 1.16mmol), Pd (} dppf) Cl 2 (43mg, 0.06 mol), was added 1,4-dioxane (4 mL) and _H 2 O (0.5mL). Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture in the microwave tube was stirred at 110 ° C. while causing a 1 h microwave reaction. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (30 mL). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a white solid (218 mg, 60% ).
MS (ESI, pos.ion) m / z: 626.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.78-8.65 (m, 2H), 8.33 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.2 Hz, 2H), 7.60-7.47 (m, 3H), 7.31 (s, 2H), 6.75 (s, 1H), 5.19 (s, 1H), 4.56 (s, 1H), 3.75 (s, 3H), 2.46 (d, J = 5.4 Hz, 1H), 2.39 (s) , 3H), 2.11 (d, J = 2.3 Hz, 1H), 1.99 (s, 1H), 1.92-1.78 (m, 2H), 1.77-1.60 (m , 5H).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] in octane-2-carboxylic acid (+/−)-trans-methyl 1,4-dioxane (5 mL) Solution of pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (215 mg, 0.3 mmol) To was added a solution of hydrogen chloride in 1,4-dioxane (4M, 0.6 mL, 2.4 mmol). The mixture was stirred at 70 ° C. overnight. After the reaction was complete, the mixture was diluted with ethyl acetate (10 mL) and the mixture was washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 15/1) to give the title compound as a pale yellow solid (125 mg, 77%).
MS (ESI, pos.ion) m / z: 472.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.78 (s, 1H), 8.64 (d, J = 9.3 Hz, 1H), 8.34 (s, 1H), 7. 84 (d, J = 4.8 Hz, 2H), 7.64 (s, 3H), 6.74 (s, 1H), 5.12 (s, 1H), 3.66 (s, 3H), 2 .74 (d, J = 5.7 Hz, 1H), 2.12 (s, 1H), 1.77 (m, 9H), 1.30 (s, 2H).

Step 5: (+/-)-Trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1H-pyrrolo [2] in a mixed solvent of methanol (2 mL), THF (2 mL) and water (2 mL)). , 3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (285 mg, 0 Sodium hydroxide (250 mg, 6.25 mmol) was added to a solution of .60 mmol). The mixture was stirred at rt overnight. After the reaction was complete, the mixture was concentrated in vacuo to remove the organic solvent. The residue was diluted with 2-methyltetrahydrofuran (10 mL) and the mixture was adjusted to pH 5.5-6.0 with dilute hydrochloric acid (1M). The resulting mixture was extracted with 2-methyltetrahydrofuran (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 50/1) to give the title compound as a pale yellow solid (120 mg, 43%).
MS (ESI, pos.ion) m / z: 458.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.64 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8 .29 (s, 1H), 8.11 (s, 2H), 7.64-7.41 (m, 4H), 6.76 (s, 1H), 4.65 (s, 1H), 2. 01 (m, 2H), 1.81 (m, 2H), 1.46 (m, 8H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 175.94, 162.91, 162.39, 156.77, 155.25, 154.46, 146.46, 138.34, 131. 76, 131.36, 130.31, 129.23, 126.76, 119.05, 115.41, 114.21, 98.26, 31.75, 29.54, 28.51, 24.18, 22.56, 21.38, 19.43.

  Example 4a: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared by the synthetic method disclosed in patent application WO2010507491. .

Step 2: 3-((2-Chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl The title compound was used as a reagent. 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride (316 mg, 1.35 mmol), 2,4-dichloro-6-phenylpyrimidine (334 mg, 1.49 mmol) ), Potassium carbonate (560 mg, 4.05 mmol), and DMF (6 mL) as a solvent, and can be prepared by the synthetic method described in Step 2 of Example 4. The title compound was a pale yellow solid (291 mg, 56%).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 3-((2-chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane. -2-carboxylic acid (2S, 3S) -ethyl (291 mg, 0.75 mmol), 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (437 mg, 1.05 mmol), potassium carbonate (207 mg, 1.50 mmol), Pd (dppf) Cl ₂ (58 mg, 0.08 mmol), 1, 4 Prepared by the synthetic method described in Step 3 of Example 4 using dioxane (5 mL) and water (0.5 mL), and the title compound was a pale yellow solid (249 mg, 52%) .

Step 4: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3] in THF / MeOH (v / v = 1/1, 6 mL)) -B] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (249 mg, 0.39 mmol) To the solution was added aqueous sodium hydroxide solution (4M, 0.98 mL, 3.90 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (109 mg, 61%).
MS (ESI, pos.ion) m / z: 458.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 458.1983 [M + H] ⁺ , (C ₂₆ H ₂₅ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 458.1992;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H) ), 8.10 (s, 2H), 7.53 (m, 4H), 6.77 (s, 1H), 4.65 (s, 1H), 1.99 (s, 2H), 1.81 (S, 2H), 1.74-1.54 (m, 4H), 1.47-1.39 (m, 2H).

  Example 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (2-fluorophenyl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (3.0 mL, 25.57 mmol) in THF (20 mL) was added palladium acetate (0. 1 g, 0.4 mmol), triphenylphosphine (0.24 g, 0.87 mmol), 2-fluorophenylboronic acid (3 g, 21 mmol) and aqueous sodium carbonate (1M, 43 mL, 43 mmol) were added. The mixture was stirred at 60 ° C. for 4 h under nitrogen protection. After the reaction was complete, the mixture was cooled to rt and concentrated in vacuo. To the residue was added H ₂ O (100 mL) and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (3.5 g, 67%).
MS (ESI, pos.ion) m / z: 243.1 [M + H] ^< +>.

Step 2: 3-((2-Chloro-6- (2-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 2,4-Dichloro-6- (2-fluorophenyl) pyrimidine (2.01 g, 8.2 mmol) and 3-aminobicyclo [2.2.2] octane-2 in N, N-dimethylformamide (10 mL) To a solution of -carboxylic acid (+/-)-trans-methyl (1.50 g, 8.2 mmol) was added potassium carbonate (1.10 g, 8 mmol). The mixture was stirred at rt overnight. After the reaction was completed, H ₂ O (40 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane) to give the title compound as a white solid (2.26 g, 71%).
MS (ESI, pos.ion) m / z: 390.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.11 (td, J = 7.8, 1.6 Hz, 1H), 7.44 (td, J = 7.3, 1.7 Hz, 1H) ), 7.26 (d, J = 7.5 Hz, 1H), 7.16 (dd, J = 11.6, 8.3 Hz, 1H), 6.89 (s, 1H), 5.37 (d , J = 4.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.76 (s, 3H), 2.39 (d, J = 5.3 Hz, 1H), 2.06 (S, 1H), 1.88 (d, J = 2.6 Hz, 1H), 1.82-1.61 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl 1,4-dioxane (15 mL) and H ₂ O (0.5 mL) in a mixed solvent of 3-(( 2-Chloro-6- (2-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (590 mg, 1.51 mmol) 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (630 mg, 1.51 mmol), potassium carbonate Beam (419 mg, 3.03 mmol) and _{Pd (dppf) Cl 2 (124mg} , 0.15mmol) was added. After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 110 ° C. while causing a microwave reaction for 1 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (20 mL). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 15/1) to give the title compound as a yellow solid (500 mg, 51 %).
MS (ESI, pos.ion) m / z: 644.2 [M + H] ⁺ ;
¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.71 (s, 1H), 8.66 (dd, J = 8.8, 2.6 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.22-8.18 (m, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.46 (dd, J = 12.2, 6.5 Hz) , 1H), 7.39 (s, 1H), 7.36 (s, 2H), 7.35 (s, 1H), 7.30 (s, 1H), 6.83 (s, 1H), 4 .95 (s, 1H), 4.73 (s, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.62 (s, 1H), 2.46 (d, J = 4.9 Hz, 1H), 2.42 (d, J = 5.0 Hz, 1H), 2.10 (d, J = 2.1 Hz, 1H), 2.00 (s, 1H), 60 (d, J = 14.8H , 1H), 1.53-1.47 (m, 1H), 1.41-1.38 (m, 1H), 1.37 (d, J = 1.3 Hz, 1H), 1.19 (s) , 1H).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl To a solution of hydrogen chloride in 1,4-dioxane (4M, 10 mL, 40 mmol) was added 3-((2- (5-fluoro -1-Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (380 mg, 0.59 mmol) was added. The mixture was stirred at 65 ° C. for 4 h. After the reaction was complete, the mixture was concentrated and the residue was diluted with ethyl acetate (10 mL). The mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a brown solid (352 mg, 75%).
MS (ESI, pos.ion) m / z: 490.3 [M + H] ^< +>.

Step 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1H) in a mixed solvent of methanol (3 mL), THF (3 mL) and water (3 mL) -Pyrrolo [2,3-b] pyridin-3-yl) -6- (2-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- To a solution of) -trans-methyl (130 mg, 0.26 mmol) was added sodium hydroxide (107 mg, 2.67 mmol). The mixture was stirred at rt overnight. After the reaction was complete, the mixture was concentrated in vacuo to remove the organic solvent and the residue was diluted with 2-methyltetrahydrofuran (10 mL). The mixture was adjusted to pH 5.5 with dilute hydrochloric acid (1 mol / L). The resulting mixture was extracted with 2-methyltetrahydrofuran (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 1/1) to give the title compound as a pale yellow solid (93 mg, 74%).
MS (ESI, pos.ion) m / z: 476.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 11.13 (s, 1H), 8.70 (dd, J = 9.2, 2.4 Hz, 1H), 8.59 (s, 1H) 8.25 (t, J = 7.1 Hz, 1H), 8.04 (s, 1H), 7.45 (dd, J = 12.9, 5.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 11.5, 8.3 Hz, 1H), 6.78 (s, 1H), 5.30 (s, 1H), 4.90 ( s, 1H), 2.56 (s, 1H), 2.20 (s, 1H), 1.95-1.65 (m, 10H).

  Example 6: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (4-fluorophenyl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (6.3 mL, 54 mmol) in THF (35 mL) was added palladium acetate (0.16 g, 0.70 mmol), triphenylphosphine (0.39 g, 1.4 mmol), p-fluorophenylboronic acid (5 g, 36 mmol) and aqueous sodium carbonate (1 mol / L, 71 mL, 71 mmol) were added. The mixture was stirred at 60 ° C. for 6 h under nitrogen protection. After the reaction was complete, the mixture was cooled to rt and concentrated in vacuo. To the residue was added H ₂ O (100 mL) and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (8.01 g, 92%).
MS (ESI, pos.ion) m / z: 242.9 [M + H] ^< +>.

Step 2: 3-((2-Chloro-6- (4-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 2,4-Dichloro-6- (4-fluorophenyl) pyrimidine (2.01 g, 8.2 mmol) and 3-aminobicyclo [2.2.2] octane-2 in N, N-dimethylformamide (10 mL) To a solution of -carboxylic acid (+/-)-trans-methyl (1.50 g, 8.2 mmol) was added potassium carbonate (1.10 g, 8 mmol). The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane) to give the title compound as a white solid (1.75 g, 55%).
MS (ESI, pos.ion) m / z: 390.1 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl 1,4-dioxane (15 mL) and H ₂ O (0.5 mL) in a mixed solvent of 3-(( 2-Chloro-6- (4-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (600 mg, 1.54 mmol) 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (640 mg, 1.53 mmol), potassium carbonate Beam (426mg, _3.08mmol), was added Pd (dppf) Cl 2 (126mg , 0.15mmol). The mixture in the microwave tube was stirred at 110 ° C. with a 1 h microwave reaction under nitrogen protection. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (20 mL). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 15/1) to give the title compound as a yellow solid (500 mg, 51 %).
MS (ESI, pos.ion) m / z: 644.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.72 (s, 1H), 8.66 (dd, J = 8.8, 2.7 Hz, 1H), 8.34 (s, 1H) 8.17-8.06 (m, 4H), 7.31 (s, 2H), 7.23 (t, J = 8.6 Hz, 2H), 6.70 (s, 1H), 3.74. (S, 3H), 3.51 (s, 1H), 2.45 (d, J = 5.1 Hz, 1H), 2.43 (d, J = 3.8 Hz, 1H), 2.39 (s , 3H), 2.13 (s, 2H), 1.99 (s, 2H), 1.93 (s, 2H), 1.85 (d, J = 11.3 Hz, 2H).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl To a solution of hydrogen chloride in 1,4-dioxane (4M, 10 mL, 40 mmol) was added 3-((2- (5-fluoro -1-Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (620 mg, 0.96 mmol) was added. The mixture was stirred at 65 ° C. for 4 h. After the reaction was complete, the mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (20 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a pale yellow solid (352 mg, 75%).
MS (ESI, pos.ion) m / z: 490.3 [M + H] ^< +>.

Step 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1H) in a mixed solvent of methanol (5 mL), THF (5 mL) and water (2 mL). -Pyrrolo [2,3-b] pyridin-3-yl) -6- (4-fluorophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- To a solution of) -trans-methyl (352 mg, 0.72 mmol) was added sodium hydroxide (290 mg, 7.25 mmol). The mixture was stirred at rt overnight. After the reaction was complete, the mixture was concentrated in vacuo and the residue was diluted with 2-methyltetrahydrofuran (10 mL). The mixture was adjusted to pH 5.5 with dilute hydrochloric acid (1M). The resulting mixture was extracted with 2-methyltetrahydrofuran (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 1/1) to give the title compound as a pale yellow solid (241 mg, 70%).
MS (ESI, pos.ion) m / z: 476.4 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.77 (dd, J = 9.6, 2.5 Hz, 1H), 8.41 (s, 1H), 8.18 (s, 1H) ), 8.12 (dd, J = 8.7, 5.5 Hz, 2H), 7.26 (t, J = 8.7 Hz, 2H), 6.74 (s, 1H), 2.59 (d , J = 4.5 Hz, 1H), 2.09 (s, 1H), 2.04 (d, J = 6.0 Hz, 2H), 1.93-1.54 (m, 8H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 175.72, 165.03, 163.23, 162.76, 158.21, 157.11, 155.48, 151.94, 146. 36, 139.67, 130.12, 128.51, 125.38, 118.92, 116.40, 116.26, 73.99, 60.43, 50.98, 49.45, 34.85, 30.89, 25.42, 21.50.

  Example 7: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrido [2,3-d] pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloropyrido [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl acetonitrile ( 15 mL), 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (405 mg, 2.21 mmol), 2,4-dichloropyrido [2,3-d]. Pyrimidine (401 mg, 2.00 mmol) and potassium phosphate (1.28 g, 6.03 mmol) were added. The mixture was stirred overnight at 80 ° C. under nitrogen protection. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (30 mL). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / MeOH (v / v) = 2/1 to 1/2) to give the title compound as a pale yellow solid (676 mg 97%).
MS (ESI, pos.ion) m / z: 347.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.97-8.89 (m, 1H), 8.48 (d, J = 7.2 Hz, 1H), 7.32 (dd, J = 8.2, 4.4 Hz, 1 H), 7.11 (s, 1 H), 4.71 (s, 1 H), 3.76 (s, 3 H), 2.65 (d, J = 4.3 Hz, 1H), 2.05 (d, J = 2.3 Hz, 1H), 1.99 (s, 1H), 1.85 (d, J = 11.0 Hz, 2H), 1.73-1.54 ( m, 5H), 1.45 (m, 1H).

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrido [2,3-d] pyrimidin-4-yl) amino) To a mixed solvent of bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl 2-methyltetrahydrofuran (5 mL) and water (1 mL) was added 5-fluoro-3- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (223 mg, 0.53 mmol), K ₃ PO ₄ (190 mg 0.90 mmol), Pd ₂ (dba) ₃ (42 mg, 0.05 mmol), 3-((2-chloropyrido [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2]. Octane-2-ca Bon acid (+/-) - trans - was added methyl (155 mg, 0.45 mmol) and XPhos (22 mg, 0.05 mmol). The mixture was stirred overnight at 78 ° C. under nitrogen protection. The mixture was diluted with ethyl acetate (40 mL) and the resulting mixture was filtered through a celite pad. After the filtrate was partitioned and the organic layer was concentrated in vacuo, the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 50 / 1-20 / 1) to give the title compound as a pale yellow Obtained as a foam (96 mg, 36%).
MS (ESI, pos.ion) m / z: 601.3 [M + H] ⁺ ;
¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 9.07 (dd, J = 4.3, 1.6 Hz, 1H), 8.93 (dd, J = 8.7, 2.8 Hz, 1H) ), 8.90 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.14 (dd, J = 8) .1, 1.5 Hz, 1H), 7.38 (dd, J = 8.1, 4.4 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 5.99 (d, J = 6.4 Hz, 1H), 5.01 (s, 1H), 3.75 (s, 3H), 2.54 (d, J = 5.5 Hz, 1H), 2.40 (s, 3H) 2.17-2.11 (m, 2H), 2.02-1.97 (m, 1H), 1.77-1.72 (m, 3H), 1.65 (m, 4H).

Step 3: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrido [2,3-d] pyrimidine-4- Il)
Amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro) in THF / MeOH / H ₂ O (v / v / v = 1/1/1, 3 mL) -1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrido [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid To a solution of acid (+/−)-trans-methyl (92 mg, 0.15 mmol) was added sodium hydroxide (62 mg, 1.55 mmol). After the mixture was stirred at rt overnight, the mixture was diluted with water (15 mL) and the resulting mixture was acidified with hydrochloric acid (1 M) to pH ˜6.0. The mixture was stirred at rt for 30 min and filtered to give the title compound as a brown solid (45 mg, 68%).
MS (ESI, pos.ion) m / z: 433.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.48 (s, 1H), 8.93 (d, J = 5.7 Hz, 2H), 8.71 (d, J = 7. 7 Hz, 1 H), 8.49 (s, 1 H), 8.41 (s, 1 H), 8.32 (s, 1 H), 7.46 (d, J = 5.1 Hz, 1 H), 4.94 (S, 1H), 3.01 (d, J = 5.9 Hz, 1H), 2.07 (s, 2H), 1.92-1.80 (m, 3H), 1.72-1.40 (M, 5H).

  Example 8: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) -4,4-dimethylpentanoic acid

Step 1: 3-Amino-4,4-dimethylpentanoic acid (R) -methyl (R) -3-Amino-4,4-dimethylpentanoic acid (1.01 g, 6.96 mmol) in methanol (60 mL). To the solution, oxalyl chloride (0.9 mL, 10 mmol) was slowly added dropwise at 0 ° C. and the mixture was maintained at this temperature and stirred for 1 h. The mixture was heated to 65 ° C. and stirred for 2 h. After the mixture was concentrated to dryness in vacuo, the residue was washed with toluene (30 mL × 3) and filtered to give the title compound as a white solid (1.11 g, 99%).
MS (ESI, pos.ion) m / z: 160.3 [M + H] ^< +>.

Step 2: 3-((2-Chloroquinazolin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl 3-amino-4,4-dimethylpentanoic acid (R) in tetrahydrofuran (20 mL) To a solution of) -methyl (700 mg, 4.39 mmol) was added DIPEA (3.63 mL, 22.0 mmol) and 2,4-dichloroquinazoline (875 mg, 4.39 mmol). The mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (907 mg, 64%).
MS (ESI, pos.ion) m / z: 322.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77-7.74 (m, 2H), 7.48 (dd, J = 11.3, 5.0 Hz, 1H), 6.93 ( d, J = 9.5 Hz, 1H), 4.85 (ddd, J = 9.7, 6.8, 4.9 Hz, 1H), 3.68 (s, 3H), 2.74 (dd, J = 15.1, 4.8 Hz, 1H), 2.64 (dd, J = 15.1, 6.9 Hz, 1H), 1.05 (s, 9H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) -4,4-dimethylpentanoic acid To a mixed solvent of (R) -methyl 1,4-dioxane (8 mL) and water (1 mL), 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 was added. -Yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (400 mg, 0.62 mmol), potassium carbonate (155 mg, 1.12 mmol), Pd (dppf) Cl ₂ (45 mg, 0.05 mmol) And 3-((2-chloroquinazolin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (180 mg, 0.56 mmol) was added. The mixture was degassed for 10 minutes by bubbling nitrogen. The mixture in the sealed tube was stirred at 110 ° C. for 2 hours. The mixture was diluted with ethyl acetate (20 mL) and the resulting mixture was filtered through a celite pad. The filtrate was partitioned and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 6/1) to give the title compound as a yellow solid (200 mg, 62%).
MS (ESI, pos.ion) m / z: 644.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.85 (dd, J = 9.0, 2.8 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8. 14 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 6.37 (d, J = 9.4 Hz, 1H), 5.06 (ddd, J = 9.2) 7.5, 5.1 Hz, 1H), 3.59 (s, 3H), 2.82 (dd, J = 14.8, 4.9 Hz, 1H), 2.68 (dd, J = 14.8) 7.5 Hz, 1H), 2.39 (s, 3H), 1.12 (s, 9H).

Step 4: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazolin-4-yl) amino) -4,4-dimethylpentanoic acid 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) quinazoline-4 in THF / MeOH (v / v = 1/1, 4 mL) To a solution of -yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (190 mg, 0.33 mmol) was added aqueous sodium hydroxide (4 M, 0.83 mL, 3.33 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to pH about 6.0, and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (55 mg, 41%).
MS (ESI, pos.ion) m / z: 408.3 [M + H] ⁺ ;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.33 (s, 1H), 8.82 (d, J = 9.6 Hz, 1H), 8.42 (d, J = 7. 5 Hz, 2H), 8.31 (s, 1H), 7.75 (s, 2H), 7.43 (s, 1H), 5.16 (m, 1H), 2.75 (d, J = 14 .6 Hz, 1H), 2.70-2.63 (m, 1H), 1.03 (s, 9H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 173.83, 160.54, 158.60, 156.92, 155.33, 146.52, 133.17, 131.90, 131. 71, 124.61, 123.58, 119.17, 119.12., 116.21, 116.07, 113.52, 55.86, 36.15, 35.86, 27.14.

  Example 9: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (furan-2-yl) pyrimidine
To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) in THF (4 mL) was added tetrakis (triphenylphosphine) palladium (43 mg, 0.05 mmol), 2-furylboronic acid (61 mg, 0.55 mol). ) And aqueous sodium bicarbonate (1M, 1.64 mL, 1.64 mmol) were added. The mixture was stirred overnight at 80 ° C. under nitrogen protection. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a green solid (42 mg, 36%).
MS (ESI, pos.ion) m / z: 215.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.67 (d, J = 0.7 Hz, 1H), 7.58 (s, 1H), 7.43 (d, J = 3.4 Hz, 1H), 6.65 (dd, J = 3.4, 1.6 Hz, 1H).

Step 2: 3-((2-Chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (429 mg, 2.34 mmol) and 2,4-dichloro-6- ( To a solution of furan-2-yl) pyrimidine (420 mg, 1.95 mmol) was added potassium carbonate (809 mg, 5.86 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (383 mg, 54%).
MS (ESI, pos.ion) m / z: 362.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.56 (s, 1H), 7.22 (s, 1H), 6.93 (s, 1H), 6.55 (d, J = 1) .6 Hz, 1H), 5.47 (d, J = 5.5 Hz, 1H), 4.44 (s, 1H), 3.70 (s, 3H), 2.44-2.33 (m, 1H) ) 1.96 (d, J = 2.5 Hz, 1H), 1.88 (s, 1H), 1.84-1.58 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a microwave tube 5-fluoro-3- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (276 mg, 0.33 mmol, 50%), 3-((2-chloro-6- (furan-2 -Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.28 mmol), potassium carbonate (114 mg, 0.83 mmol) ), Pd (dpp _{) Cl 2 (45mg, 0.06mmol)} , was charged 1,4-dioxane (3 mL) and _H 2 O (0.2mL). The resulting solution was bubbled with nitrogen for 10 minutes to remove air, and then the mixture in the tube was subjected to a microwave reaction at 110 ° C. for 2 h. The reaction mixture was passed through celite and the filter cake was washed with EtOAc (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (72 mg, 42%).
MS (ESI, pos.ion) m / z: 616.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.70-8.64 (m, 2H), 8.33 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.59 (s, 1H), 7.30 (s, 1H), 7.26 (d, J = 3.2 Hz, 1H), 6.67 (s, 1H), 6 .60 (dd, J = 3.3, 1.7 Hz, 1H), 4.76 (s, 1H), 3.75 (s, 3H), 2.45 (s, 1H), 2.39 (s , 3H), 2.10 (s, 1H), 1.98 (s, 1H), 1.42 (m, 8H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl) in THF / MeOH (v / v = 1/1, 4 mL) -1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( To a solution of +/−)-trans-methyl (75 mg, 0.12 mmol) was added aqueous NaOH (4M, 0.30 mL, 1.20 mmol) and the resulting mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the mixture and the resulting mixture was adjusted to pH˜5.5 with HCl (1M). The mixture was then extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (35 mg, 64%).
MS (ESI, pos.ion) m / z: 472.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 448.1776 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₃ ) [M + H] ⁺ Theoretical: 448.1785;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H) ), 7.88 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 4.62 (S, 1H), 1.99 (s, 2H), 1.83-1.33 (m, 10H).

  Example 9a: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl As a reagent, 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -methyl hydrochloride (331 mg, 1.42 mmol), 2,4-dichloro-6- (furan Prepared by the synthetic method described in Step 2 of Example 9, using 2-yl) pyrimidine (278 mg, 1.29 mmol), potassium carbonate (590 mg, 4.26 mmol), and DMF (6 mL) as solvent. Can do. The title compound was a pale yellow solid (247 mg, 51%).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 3-((2-chloro-6- (furan-2-yl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (78 mg, 0.21 mmol), 5-fluoro-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (203 mg, 0.29 mmol, 60%), potassium carbonate (87 mg, 0.63 mmol), Pd _(dppf) Cl 2 (15mg 0.02 mmol), 1,4-dioxane (3 mL) and with water (0.2 mL), may be prepared by synthetic methods described in step 3 of Example 9. The title compound was a pale yellow solid (81 mg, 61%).

Step 4: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl-1H) in THF / EtOH (v / v = 1/1, 4 mL) -Pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, To a solution of 3S) -ethyl (81 mg, 0.13 mmol) was added aqueous sodium hydroxide (4M, 0.33 mL, 1.30 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (35 mg, 64%).
MS (ESI, pos.ion) m / z: 448.5 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 448.1762 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₃ ) [M + H] ⁺ Theoretical: 448.1785;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.29 (s, 1 H), 8.62 (s, 1 H), 8.33 (s, 1 H), 8.28 (s, 1 H ), 7.88 (s, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 6.69 (s, 1H), 6.65 (s, 1H), 4.63 (S, 1H), 1.99 (s, 2H), 1.80-1.38 (m, 8H).

  Example 10: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-phenylethynyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (2-phenylethynyl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (101 mg, 0.55 mmol) in toluene (3 mL) was added tributyl (2-phenylethynyl). Stannane (259 mg, 0.66 mmol), triphenylarsine (67 mg, 0.22 mmol), Pd (PPh ₃ ) Cl ₂ (40 mg, 0.06 mmol) were added. The reaction mixture was heated to 80 ° C. and stirred for 6 h under nitrogen protection. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (129 mg, 94%).
MS (ESI, pos.ion) m / z: 249.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.40 (t, J = 7.9 Hz, 2H), 8.29 (d, J = 8.7 Hz, 1H), 7.88-7. 74 (m, 2H).

Step 2: 3-((2-Chloro-6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl DMF ( 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (405 mg, 2.21 mmol) and 2,4-dichloro-6- (phenylethynyl) in 5 mL) To a solution of pyrimidine (500 mg, 2.01 mmol) was added potassium carbonate (306 mg, 2.21 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO _{4 and} concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (470 mg, 59%).
MS (ESI, pos.ion) m / z: 396.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.59 (d, J = 6.8 Hz, 2H), 7.41-7.37 (m, 3H), 6.55 (s, 1H) 5.50 (s, 1H), 3.76 (s, 3H), 2.36 (d, J = 5.3 Hz, 1H), 1.84 (s, 1H), 1.70-1.42 (M, 10H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid (+/-)-trans-methyl Into a microwave tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (253 mg, 0.30 mmol, 50%), 3-((2-chloro-6- (phenylethynyl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.25 mmol), potassium carbonate (105 mg, 0.76 mmol), Pd (dpp _{f) Cl 2 (42mg, 0.05mmol} ), was charged 1,4-dioxane (3 mL) and _H 2 O a (0.2 mL). After the resulting mixture was bubbled with nitrogen for 3 minutes to remove air, the mixture in the tube was subjected to a microwave reaction at 110 ° C. for 2 h. The reaction mixture was passed through celite and the filter cake was washed with EtOAc (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (37 mg, 23%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.70 (s, 1H), 8.65 (dd, J = 8.8, 2.7 Hz, 1H), 8.32 (s, 1H) 8.12 (d, J = 8.3 Hz, 2H), 7.73 (dd, J = 5.6, 3.4 Hz, 2H), 7.69-7.63 (m, 2H), 7. 55 (dd, J = 5.6, 3.3 Hz, 2H), 7.43 (s, 1H), 7.31 (s, 1H), 6.52 (s, 1H), 3.81 (s, 1H), 3.75 (s, 3H), 2.42 (s, 1H), 2.39 (s, 3H), 2.11 (s, 1H), 1.97 (s, 1H), 1. 80-1.64 (m, 8H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-phenylethynyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl-) in THF / MeOH (v / v = 1/1, 2 mL) 1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) To a solution of trans-methyl (37 mg, 0.06 mmol) was added aqueous NaOH (4M, 0.15 mL, 0.60 mmol) and the mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the mixture and the resulting mixture was adjusted to pH˜5.5 with HCl (1M) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ and filtered, then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (19 mg, 69%).
MS (ESI, pos.ion) m / z: 482.5 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.33 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.38 (t, J = 9.5 Hz, 4 H), 8.30 (s, 1 H), 7.66 (s, 1 H), 6.88 (s, 1 H), 4.71 (s, 1 H), 2.67 (s, 1H), 2.33 (s, 1H), 1.44 (s, 8H).

  Example 10a: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-phenylethynyl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -methyl hydrochloride (386 mg, 1.65 mmol), 2,4-dichloro-6- (phenylethynyl) pyrimidine as reagents (410 mg, 1.65 mmol), potassium carbonate (684 mg, 4.95 mmol), and DMF (5 mL) as a solvent can be prepared by the synthetic method described in Step 2 of Example 10. The title compound was a yellow solid (458 mg, 68%).
MS (ESI, pos.ion) m / z: 410.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.63-7.57 (m, 2H), 7.43-7.36 (m, 3H), 6.57 (s, 1H), 5 .50 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.34 (d, J = 5.1 Hz, 1H), 2.09 (s, 1H), 1.85 (D, J = 2.4 Hz, 1H), 1.78-1.63 (m, 6H), 1.57 (d, J = 9.8 Hz, 2H), 1.29 (t, J = 7. 1Hz, 3H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2 as a reagent. -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (541 mg, 0.59 mmol, 45%), 3-((2-chloro-6- (phenylethynylpyrimidine-4) -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (200 mg, 0.49 mmol), potassium carbonate (202 mg, 1.46 mmol) and Pd (dppf) C Prepared by the synthetic method described in Step 3 of Example 10, using l ₂ (79 mg, 0.10 mmol) and a mixture of 1,4-dioxane (3 mL) and water (0.2 mL) as the mixed solvent. The title compound was a yellow solid (46 mg, 14%).
MS (ESI, pos.ion) m / z: 664.2 [M + H] ^< +>.

Step 4: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (2-phenylethynyl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid The title compound is 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3 -Yl) -6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (46 mg, 0.07 mmol), aqueous NaOH ( 4M, 0.18 mL, 0.70 mmol) and a mixed solvent THF / MeOH (v / v = 1/1, 2 mL) can be prepared by the synthetic method described in Step 4 of Example 10. . The title compound was a yellow solid (10 mg, 30%).
MS (ESI, pos.ion) m / z: 482.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.35 (s, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.28 (s, 2H), 7 .93 (s, 1H), 7.64 (s, 2H), 7.49 (s, 3H), 6.58 (s, 1H), 4.64 (s, 1H), 2.56 (s, 1H), 1.87-1.49 (m, 10H).

  Example 11: (+/−)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenoxypyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-dichloro-6-phenoxypyrimidine
To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in acetone (6 mL), slowly add a mixture of phenol (257 mg, 2.73 mmol) and NaOH (112 mg, 2.78 mmol) at 0 ° C. It was dripped. The mixture was stirred at room temperature for 3 h. 30 mL of H ₂ O was then added to the mixture. The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a colorless oil (569 mg, 87%).
MS (ESI, pos.ion) m / z: 249.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.18-7. 14 (m, 2H), 6.80 (s, 1H).

Step 2: 3-((2-Chloro-6-phenoxypyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in DMF (5 mL) Of 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (460 mg, 2.51 mmol) and 2,4-dichloro-6-phenoxy-pyrimidine (550 mg, 2 .28 mmol) was added potassium carbonate (346 mg, 2.51 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO _{4 and} concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 1/1) to give the title compound as a white solid (386 mg, 44%).
MS (ESI, pos.ion) m / z: 388.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.59 (d, J = 6.8 Hz, 2H), 7.41-7.37 (m, 3H), 6.55 (s, 1H) 5.50 (s, 1H), 3.76 (s, 3H), 2.36 (d, J = 5.3 Hz, 1H), 1.84 (s, 1H), 1.70-1.42 (M, 10H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenoxypyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl In a sealed tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (258 mg, 0.31 mmol, 50%), 3-((2-chloro-6-phenoxypyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) - trans - methyl (100 mg, 0.26 mmol), potassium carbonate (106mg, 0.77mmol), Pd ( dppf) Cl 2 (42mg 0.05 mmol), was charged 1,4-dioxane (3 mL) and _H 2 O a (0.2 mL). The resulting mixture in a sealed tube was stirred at 110 ° C. for 3 h under nitrogen protection. The reaction mixture was passed through celite and the filter cake was washed with EtOAc (50 mL). The filtrate was washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (80 mg, 48%).
MS (ESI, pos.ion) m / z: 642.6 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.45 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 8 .3 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.31 (d, J = 8.3 Hz, 3H), 7.20 (d, J = 7.8 Hz, 2H) 6.39 (s, 1H), 5.16 (s, 1H), 4.64 (s, 1H), 3.64 (s, 3H), 2.40 (s, 3H), 2.32 ( d, J = 6.3 Hz, 1H), 2.01 (s, 1H), 1.71 (d, J = 11.5 Hz, 2H), 1.55-1.30 (m, 6H).

Step 4: (+/-)-Trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenoxypyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl-1H-) in a mixed solvent of THF / MeOH (v / v = 1/1, 3 mL) Pyrrolo [2,3-b] pyridin-3-yl) -6-phenoxypyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl ( To a solution of 173 mg, 0.27 mmol) was added aqueous NaOH (4M, 0.67 mL, 2.70 mmol) and the mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the mixture and the resulting mixture was adjusted to pH˜5.5 with HCl (1M). The mixture was then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ and filtered, then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (70 mg, 55%).
MS (ESI, pos.ion) m / z: 474.1 [M + H] ⁺ ;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.37 (s, 1H), 12.20 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H) ), 7.43 (s, 2H), 7.29-7.17 (m, 3H), 7.10 (d, J = 5.0 Hz, 1H), 6.73 (s, 1H), 4. 55 (s, 1H), 3.60 (s, 1H), 3.36 (s, 3H), 2.68 (s, 1H), 1.77 (m, 8H).

  Example 12: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazole- 4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (1-methyl-1H-pyrazol-4-yl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) in THF (4 mL), Pd (PPh ₃ ) ₂ Cl ₂ (38 mg, 0.05 mmol), (1-methylpyrazol-4-yl) boronic acid (68 mg, 0.55 mol) and aqueous Na ₂ CO ₃ (1M, 1.10 mL, 1. 10 mmol) was added. The reaction mixture was heated to 70 ° C. under nitrogen protection and stirred for 4 h. 50 mL of water was then added to the mixture. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and then the filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (94 mg, 75%).
MS (ESI, pos.ion) m / z: 229.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.12 (s, 1H), 8.03 (s, 1H), 7.34 (s, 1H), 4.00 (s, 3H).

Step 2: 3-((2-Chloro-6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ /-)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (88 mg, 0.48 mmol) in DMF (2 mL), 2,4 To a solution of -dichloro-6- (1-methyl-1H-pyrazol-4-yl) pyrimidine (92 mg, 0.40 mmol) was added potassium carbonate (167 mg, 1.20 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1/1) to give the title compound as a white solid (87 mg, 58%).
MS (ESI, pos.ion) m / z: 376.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (s, 1H), 7.94 (s, 1H), 6.52 (s, 1H), 5.37 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 2.38 (d, J = 5.0 Hz, 1H), 2.07 (d, J = 5.7 Hz, 1H), 1. 86 (d, J = 2.6 Hz, 1H), 1.49 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl in a microwave tube 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (231 mg, 0.28 mmol, 50%), 3-((2-chloro- 6- (1-Methylpyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (87 mg, 0.23 mmol) , Potassium acetate (95 mg, 0 .69 mmol), Pd (dppf) Cl ₂ (37 mg, 0.05 mmol), 1,4-dioxane (3 mL) and H ₂ O (0.2 mL) were charged. After the resulting mixture was bubbled with nitrogen for 10 minutes, the mixture was stirred at 110 ° C. for 2 h with microwave heating. The reaction mixture was filtered through a celite pad and the filter cake was washed with EtOAc (50 mL). The filtrate was washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a brown solid (54 mg, 37%).
MS (ESI, pos.ion) m / z: 630.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.66 (s, 1H), 8.63 (dd, J = 8.9, 2.6 Hz, 1H), 8.33 (s, 1H) 8.12 (d, J = 8.2 Hz, 2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.30 (s, 1H), 6.47 (s, 1H) ), 5.15 (s, 1H), 4.49 (s, 1H), 4.03 (s, 3H), 3.74 (s, 3H), 2.43 (d, J = 5.1 Hz, 1H), 2.39 (s, 3H), 2.10 (s, 1H), 1.97 (s, 1H), 1.52-1.39 (m, 8H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazole- 4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid in THF / MeOH (v / v = 1/1, 3 mL) 3-((2- (5 -Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (54 mg, 0.09 mmol) was added aqueous NaOH (4 M, 0.23 mL, 0.90 mmol) and the mixture was Stir at 30 ° C. overnight. Water (10 mL) was added to the mixture and the resulting mixture was adjusted to pH˜5.5 with HCl (1M). The mixture was then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (17 mg, 43%).
MS (ESI, pos.ion) m / z: 462.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 462.0262 [M + H] ⁺ , (C ₂₄ H ₂₅ FN ₇ O ₂ ) [M + H] ⁺ Theoretical: 462.2054;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.23 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H) ), 7.99 (s, 1H), 7.31 (s, 1H), 6.43 (s, 1H), 4.61 (s, 1H), 3.92 (s, 3H), 1.98. (S, 1H), 1.79 (s, 1H), 1.74-1.26 (m, 8H).

  Example 13: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrrole- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (1-methyl-1H-pyrrol-3-yl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in THF (20 mL), Pd (PPh ₃ ) ₂ Cl ₂ (191 mg, 0.27 mmol), (1-methylpyrrol-3-yl) boronic acid (627 mg, 2.73 mol) and aqueous Na ₂ CO ₃ (1M, 5.45 mL, 5. 45 mmol) was added. The reaction mixture was heated to 70 ° C. and stirred for 4 h under nitrogen protection. 50 mL of water was then added to the mixture. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (484 mg, 78%).
MS (ESI, pos.ion) m / z: 228.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48 (s, 1H), 7.25 (s, 1H), 6.70-6.58 (m, 2H), 3.73 (s , 3H).

Step 2: 3-((2-Chloro-6- (1-methyl-1H-pyrrol-3-yl) pyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+ /-)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (466 mg, 2.54 mmol) in DMF (6 mL), 2,4 To a solution of -dichloro-6- (1-methylpyrrol-3-yl) pyrimidine (484 mg, 2.12 mmol) was added potassium carbonate (879 mg, 6.36 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO _{4 and} concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (234 mg, 29%).
MS (ESI, pos.ion) m / z: 375.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39 (s, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 6.44 (s, 1H), 5.32 (s, 2H), 4.24 (d, J = 5.8 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.37 (d, J = 4.8 Hz, 1H), 1.86 (d, J = 2.5 Hz, 1H), 1.71-1.40 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrrol-3-yl) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl in a microwave tube 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (647 mg, 0.78 mmol), 3-((2-chloro-6- ( 1-methylpyrrol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (243 mg, 0.65 mmol), potassium acetate (268 mg, 1.95 m mol), Pd (dppf) Cl ₂ (105 mg, 0.13 mmol), 1,4-dioxane (3 mL) and H ₂ O (0.2 mL). The resulting mixture was bubbled with nitrogen for 10 minutes and stirred at 110 ° C. for 2 h with microwave heating. The reaction mixture was filtered through a celite pad and the filter cake was washed with EtOAc (50 mL). The resulting filtrate was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a brown solid (330 mg, 81%).
MS (ESI, pos.ion) m / z: 629.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.70-8.61 (m, 2H), 8.31 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H) 7.42 (s, 1H), 7.27 (s, 1H), 6.67 (s, 2H), 6.43 (s, 1H), 5.32 (s, 1H), 3.80 ( s, 3H), 3.76 (s, 3H), 2.43 (d, J = 5.0 Hz, 1H), 2.38 (s, 3H), 1.96 (s, 1H), 1.73 (S, 10H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrrole- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5) in THF / MeOH (v / v = 1/1, 3 mL) -Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrrol-3-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (330 mg, 0.52 mmol) was added aqueous NaOH (4 M, 1.30 mL, 5.20 mmol) and obtained The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the mixture and the resulting mixture was adjusted to pH˜5.5 with HCl (1M). The mixture was then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (42 mg, 17%).
MS (ESI, pos.ion) m / z: 461.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 461.2114 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₃ ) [M + H] ⁺ Theoretical value: 461.2101;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.63 (s, 1H), 8.27 (s, 2H), 7.51 (s, 1H) ), 7.28 (s, 1H), 6.81 (s, 1H), 6.55 (s, 1H), 6.41 (s, 1H), 4.60 (s, 1H), 3.62 (S, 3H), 2.03-1.30 (m, 10H).

  Example 14: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl)-[4,5'-bipyrimidine] -6- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,6-Dichloro-4,5′-bipyrimidine To a solution of 2,4,6-trichloropyrimidine (100 mg, 0.55 mmol) in acetonitrile (4 mL) was added Pd (dppf) Cl ₂ (89 mg, 0 .11 mmol), pyrimidin-5-ylboronic acid (67 mg, 0.55 mol), CsCO ₃ (266 mg, 0.82 mmol) and H ₂ O (0.5 mL) were added. The reaction mixture was heated to 95 ° C. under nitrogen protection and stirred for 5 h. 50 mL of water was then added to the mixture. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO _{4 and} concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a red solid (44 mg, 36%).
MS (ESI, pos.ion) m / z: 228.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.41 (s, 3H), 7.76 (s, 1H).

Step 2: 3-((2-Chloro- [4,5′-bipyrimidin] -6-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl DMF 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (73 mg, 0.40 mmol), 2,6-dichloro-4,5′- in (2 mL). To a solution of bipyrimidine (76 mg, 0.33 mmol) was added potassium carbonate (138 mg, 1.00 mmol). The mixture was then stirred overnight at room temperature. Water (40 mL) was added to the mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and dried. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1/1) to give the title compound as a white solid (65 mg, 52%).
MS (ESI, pos.ion) m / z: 374.4 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.32 (s, 3H), 6.95 (s, 1H), 5.77 (s, 1H), 4.36 (s, 1H), 3.77 (s, 3H), 2.41 (d, J = 3.4 Hz, 1H), 1.88 (s, 1H), 1.83 to 1.65 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl)-[4,5′-bipyrimidin] -6-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl In a microwave tube 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (173 mg, 0.21 mmol, 50%), 3-((2-chloro- [4,5′-bipyrimidine] -6-yl) amino) bicycle [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (65 mg, 0.17 mmol), potassium acetate (72 mg, 0.52 mmol), Pd ( _dppf) Cl 2 (28mg, .03mmol), it was charged 1,4-dioxane (3 mL) and water (0.2 mL). The resulting solution was bubbled with nitrogen for 10 minutes to remove air, and then stirred at 110 ° C. for 2 hours while being heated with microwaves. The reaction mixture was filtered through a celite pad and the filter cake was washed with EtOAc (50 mL). The filtrate was washed with saturated brine (50 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a brown solid (50 mg, 46%).
MS (ESI, pos.ion) m / z: 628.7 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.41 (s, 2H), 9.35 (s, 1H), 8.73 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 8.3 Hz, 2H), 5.37 (s, 1H), 3.76 (s, 3H), 2.46 (s, 1H), 2.40 (s, 3H) 2.14 (s, 1H), 2.05-1.99 (m, 2H), 1.49-1.41 (m, 8H).

Step 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl)-[4,5'-bipyrimidine] -6- Yl) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo) in THF / MeOH (v / v = 1/1, 2 mL) [2,3-b] pyridin-3-yl)-[4,5′-bipyrimidin] -6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans To a solution of methyl (50 mg, 0.08 mmol) was added aqueous NaOH (4 M, 0.2 mL, 0.80 mmol) and the mixture was stirred overnight at 30 ° C. Water (10 mL) was added to the mixture, The mixture was adjusted with HCl (1M) to a pH of about 5.5. Was washed with EtOAc and extracted with (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous _Na 2 SO _4, and the filtered. The filtrate was concentrated in vacuo to remove the solvent. The resulting The resulting residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (20 mg, 55%).
MS (ESI, pos.ion) m / z: 460.5 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 460.1905 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₇ O ₂ ) [M + H] ⁺ Theoretical value: 460.1897;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.36 (s, 1H), 9.60 (s, 1H), 9.44 (s, 1H), 9.31 (s, 1H) ), 8.60 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.78 (s, 1H), 6.88 (s, 1H), 4.69. (S, 1H), 2.01 (s, 2H), 1.88-1.32 (m, 8H).

  Example 15: (+/-)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide

Step 1: (+/-)-cis-3-tert-butoxycarbonylamino-1-benzyloxycarbonylaminocyclohexane (+/-)-cis-3-((tert-butoxycarbonyl) amino in toluene (60 mL) ) To a solution of cyclohexanecarboxylic acid (5 g, 20.6 mmol) triethylamine (4.6 mL, 33.0 mmol) and diphenylphosphoryl azide (5.32 mL, 24.7 mmol) were added and the mixture was stirred at rt for 3 h. Benzyl alcohol (4.27 mL, 41.1 mmol) was then added and the resulting mixture was stirred at 100 ° C. overnight under nitrogen protection. The reaction mixture was diluted with ethyl acetate (60 mL) and the resulting mixture was washed with saturated brine (60 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a dark yellow oil (7.16 g, 100%).

Step 2: (+/-)-cis-N-tert-butoxycarbonyl-1,3-cyclohexanediamine (+/-)-cis-3-tert-butoxycarbonylamino-1-benzyloxy in methanol (100 mL) A solution of carbonylaminocyclohexane (7.2 g, 21 mmol) was placed in the autoclave and Pd / C (10% Pd, 2 g) was added to the solution. The resulting mixture was stirred overnight at rt in a hydrogen atmosphere under a pressure of 2 MPa. After filtering the reaction mixture through a celite pad to remove the catalyst, the filter cake was washed with a mixture of methanol (200 mL) and ethyl acetate (200 mL). The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1-10 / 1) to give the title compound as a colorless oil ( 1.65 g, 37%).
MS (ESI, pos.ion) m / z: 215.1 [M + H] ^< +>.

Step 3: 2,4-Dichloro-6-phenylpyrimidine To a solution of 2,4,6-trichloropyrimidine (0.29 mL, 2.5 mmol) in tetrahydrofuran (5 mL), palladium acetate (8 mg, 0.035 mmol), Triphenylphosphine (18 mg, 0.065 mmol), phenylboronic acid (0.20 g, 1.6 mmol) and aqueous sodium carbonate (1M, 3.3 mL, 3.3 mmol) were added. The mixture was stirred at 60 ° C. for 6 h, then cooled to rt and concentrated to remove the organic solvent. To the residue was added H ₂ O (10 mL) and the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (0.225 g, 61%).
MS (ESI, pos.ion) m / z: 224.95 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.15-8.04 (m, 2H), 7.70 (s, 1H), 7.63-7.50 (m, 3H).

Step 4: (3-((2-Chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) carbamic acid (+/-)-cis-tert-butyl 2 in N, N-dimethylformamide (5 mL) , 4-Dichloro-6-phenylpyrimidine (727 mg, 3.23 mmol) and (+/-)-cis-N-tert-butoxycarbonyl-1,3-cyclohexanediamine (630 mg, 2.94 mmol) in a solution of carbonic acid. Potassium (1.22 g, 8.82 mmol) was added. The mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (516 mg, 43%).
MS-ESI: (ESI, pos.ion) m / z: 403.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02-7.93 (m, 2H), 7.53-7.44 (m, 3H), 6.59 (s, 1H), 4 .45 (s, 1H), 3.60 (s, 1H), 2.43 (d, J = 11.8 Hz, 1H), 2.10 (d, J = 14.5 Hz, 2H), 1.89 (D, J = 14.0 Hz, 1H), 1.63 (s, 4H), 1.57-1.43 (m, 11H).

Step 5: To a hydrochloric acid solution (1.1 mL, 5.5 mmol, 5 mol / L) in N ^1- (2-chloro-6-phenylpyrimidin-4-yl) cyclohexane-1,3-diamine 1,4-dioxane , (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) carbamic acid (+/-)-cis-tert-butyl (220 mg, 0.55 mmol) was added and the mixture was And stirred overnight. The reaction mixture was concentrated in vacuo to remove the solvent and an appropriate amount of water was added to the residue. The resulting mixture was adjusted to pH 9 with saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to dryness in vacuo to give the title compound as a white solid (144 mg, 87%).
MS (ESI, pos.ion) m / z: 303.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.9-7.89 (m, 2H), 7.58-7.41 (m, 3H), 6.57 (s, 1H), 5 .74 (s, 1H), 2.25-2.14 (m, 1H), 2.00 (d, J = 13.2 Hz, 1H), 1.88 (d, J = 9.8 Hz, 2H) 1.58-1.37 (m, 2H), 1.30-1.12 (m, 4H).

Step 6: (+/-)-cis-N- (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide tetrahydrofuran To a solution of N ^1- (2-chloro-6-phenylpyrimidin-4-yl) cyclohexane-1,3-diamine (65 mg, 0.21 mmol) in a mixed solvent of (4 mL) and dimethyl sulfoxide (1 mL) , N-diisopropylethylamine (0.11 mL, 0.7 mmol) and 1H-1,2,3-triazole-4-carboxylic acid (48 mg, 0.42 mmol) were added. After the mixture was stirred at rt for 10 min, HATU (163 mg, 0.43 mmol) was added and the resulting mixture was stirred at rt for 3 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (85 mg, 100%).
MS (ESI, pos.ion) m / z: 398.5 [M + H] ^< +>.

Step 7: (+/-)-cis-N- (3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine -4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide
To a microwave tube, add 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b]. Pyridine (652 mg, 0.55 mmol, 50%), (+/−)-cis-N- (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1H-1,2, , 3-triazole-4-carboxamide (85 mg, 0.21 mmol), potassium carbonate (88 mg, 0.64 mmol), Pd (dppf) Cl ₂ (34 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) was added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (139 mg, 100%) .
MS (ESI, pos.ion) m / z: 652.2 [M + H] ^< +>.

Step 8: (+/-)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide (+/-)-cis-N- (3-((2- (5-fluoro-1-tosyl) in methanol (1 mL) -1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide (192 mg, 0. 1). To a solution of 29 mmol) was added a solution of sodium methoxide in methanol (5M, 0.6 mL, 2.9 mmol). The mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated in vacuo to dryness and water (10 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (20 mL × 3) and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (25 mg, 60%).
MS (ESI, pos.ion) m / z: 498.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 488.2169 [M + H] ⁺ , (C ₂₆ H ₂₅ FN ₉ O) [M + H] ⁺ Theoretical: 498.2166;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.29 (s, 1H), 8.58 (s, 1H), 8.41 (s, 2H), 8.29 (s, 1H) ), 8.11 (s, 2H), 7.58-7.48 (m, 3H), 7.42 (s, 1H), 6.76 (s, 1H), 4.15 (s, 1H) 4.04 (s, 1H), 2.30-1.79 (m, 6H).

  Example 16: (+/-)-trans-3-((6- (benzofuran-2-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 4- (Benzofuran-2-yl) -2,6-dichloropyrimidine A solution of 2,4,6-trichloropyrimidine (50 mg, 0.27 mmol) in a mixed solvent of toluene (3 mL) and ethanol (1 mL). To was added tetrakis (triphenylphosphine) palladium (31 mg, 0.03 mmol), benzofuran-2-ylboronic acid (44 mg, 0.28 mmol) and aqueous sodium carbonate (1M, 0.82 mL, 0.82 mmol). The mixture was stirred at 85 ° C. for 4 h under nitrogen protection. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (26 mg, 36%).
MS (ESI, pos.ion) m / z: 265.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, J = 4.1 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H).

Step 2: 3-((6- (Benzofuran-2-yl) -2-chloropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (628 mg, 3.43 mmol) and 4- (benzofuran-2-yl) -2,6-dichloro After pyrimidine (758 mg, 2.86 mmol) was dissolved in DMF (5 mL), potassium carbonate (1.19 g, 8.58 mmol) was added. The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a white solid (553 mg, 47%).
MS (ESI, pos.ion) m / z: 412.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.68 (d, J = 7.5 Hz, 1H), 7.62-7.54 (m, 2H), 7.40 (dd, J = 9.4, 5.9 Hz, 2H), 6.91 (s, 1H), 5.57 (s, 1H), 4.36 (s, 1H), 3.78 (s, 3H), 2.40. (D, J = 5.2 Hz, 1H), 2.34 (d, J = 3.7 Hz, 1H), 1.90 (d, J = 2.6 Hz, 1H), 1.85 to 1.69 ( m, 8H).

Step 3: 3-((6- (Benzofuran-2-yl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl microwave tube with 5-fluoro-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (455 mg, 0.44 mmol, 50%), 3-((6- (benzofuran-2-yl)) -2-chloropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (166 mg, 0.40 mmol), potassium carbonate (165 mg, 1. 20 mmol), Pd (dppf) Cl ₂ (65 mg, 0.08 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (57 mg, 35%) .
MS (ESI, pos.ion) m / z: 666.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.77-8.67 (m, 2H), 8.35 (d, J = 1.7 Hz, 1H), 8.15 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.40 ( d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.2 Hz, 3H), 6.89 (s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.77 (s, 3H), 2.47 (d, J = 5.5 Hz, 1H), 2.40 (s, 3H), 2.12 (s, 1H), 2.01 (s) , 1H), 1.97-1.62 (m, 8H).

Step 4: (+/-)-trans-3-((6- (benzofuran-2-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (benzofuran-2-yl)-in THF / MeOH (v / v = 1/1, 2 mL)) 2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( To a solution of +/−)-trans-methyl (57 mg, 0.09 mmol) was added aqueous sodium hydroxide (4M, 0.23 mL, 0.90 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (22 mg, 52%).
MS (ESI, pos.ion) m / z: 498.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 498.1931 [M + H] ⁺ , (C ₂₈ H ₂₅ FN ₅ O ₃ ) [M + H] ⁺ Theoretical value: 498.1941;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.33 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.38 (t, J = 9.5 Hz, 4 H), 8.30 (s, 1 H), 7.66 (s, 1 H), 6.88 (s, 1 H), 4.71 (s, 1 H), 2.67 (s, 1H), 2.33 (s, 1H), 1.79-1.41 (m, 8H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 185.05, 162.79, 162.67, 155.32, 155.14, 154.87, 152.39, 146.48, 131. 92, 131.87, 131.66, 128.61, 126.28, 123.98, 122.63, 119.01, 111.88, 106.59, 67.49, 50.06, 29.49, 28.75, 28.45, 25.60, 24.20, 21.38, 19.43.

  Example 17: (+/-)-trans-3-((6- (benzo [b] thiophen-2-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 4- (Benzo [b] thiophen-2-yl) -2,6-dichloropyrimidine 2,4,6-Trichloropyrimidine (50 mg, 0. 0) in a mixed solvent of toluene (3 mL) and ethanol (1 mL). 27 mmol) was added to tetrakis (triphenylphosphine) palladium (31 mg, 0.03 mmol), benzo [b] thiophen-2-ylboronic acid (49 mg, 0.28 mmol) and aqueous sodium carbonate (1M, 0.82 mL, 0 .82 mmol) was added. The mixture was stirred at 85 ° C. for 4 h under nitrogen protection. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (24 mg, 31%).
MS (ESI, pos.ion) m / z: 280.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (s, 1H), 7.91 (t, J = 6.4 Hz, 2H), 7.64 (s, 1H), 7.51 -7.43 (m, 2H).

Step 2: 3-((6- (Benzo [b] thiophen-2-yl) -2-chloropyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (409 mg, 2.23 mmol) and 4- (benzo [b] thiophene-2- Yl) -2,6-dichloropyrimidine (523 mg, 1.86 mmol) was dissolved in DMF (5 mL), and then potassium carbonate (771 mg, 5.58 mmol) was added. The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a white solid (357 mg, 45%).
MS (ESI, pos.ion) m / z: 428.6 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.05 (s, 1H), 7.91-7.81 (m, 2H), 7.43-7.36 (m, 2H), 6 .80 (s, 1H), 5.50 (s, 1H), 4.35 (s, 1H), 3.78 (s, 3H), 2.41 (d, J = 4.9 Hz, 1H), 2.10 (s, 1H), 1.90 (d, J = 2.6 Hz, 1H), 1.84-1.63 (m, 6H), 1.58-1.43 (m, 2H).

Step 3: 3-((6- (Benzo [b] thiophen-2-yl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a microwave tube, 5-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (233 mg, 0.28 mmol), 3-((6- (benzo [b] thiophene -2-yl) -2-chloropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.23 mmol), potassium carbonate (96mg, 0.70m mol), Pd (dppf) Cl ₂ (38 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (147 mg, 92%) .
MS (ESI, pos.ion) m / z: 682.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.79 (dd, J = 9.0, 2.8 Hz, 1H), 8.71 (s, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.99 (s, 1H), 7.96-7.92 (m, 1H), 7.90-7. 85 (m, 1H), 7.44-7.39 (m, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.80 (s, 1H), 5.28 (s, 1H), 4.55 (s, 1H), 3.77 (s, 3H), 2.47 (d, J = 5.2 Hz, 1H), 2.40 (s, 3H), 2.12 (s , 1H), 1.99 (s, 1H), 1.92-1.63 (m, 8H).

Step 4: (+/-)-trans-3-((6- (benzo [b] thiophen-2-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid in THF / MeOH (v / v = 1/1, 2 mL) 3-((6- (benzo [b ] Thiophen-2-yl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] ] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (147 mg, 0.22 mmol) was added aqueous sodium hydroxide (4 M, 0.55 mL, 2.20 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (54 mg, 49%).
MS (ESI, pos.ion) m / z: 514.2 [M + 1] +;
HRMS (ESI, pos.ion) m / z: 514.1710 [M + H] ⁺ , (C ₂₄ H ₂₅ FN ₇ O ₂ ) [M + H] ⁺ Theoretical: 514.1713;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.32 (s, 1H), 8.69 (s, 1H), 8.34 (s, 1H), 8.32 (s, 1H) ), 8.11 (s, 1H), 8.09-8.05 (m, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.43 (dd, J = 5.8, 3.1 Hz, 2H), 6.85 (s, 1H), 4.62 (s, 1H), 1.99 (s, 2H), 1.84-1.40 (m, 8H) ;
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 175.97, 162.74, 162.41, 157.35, 154.96, 146.50, 144.31, 140.47, 140. 21, 131.98, 131.69, 125.96, 125.21, 124.98, 123.21, 119.04, 118.97, 114.52, 50.72, 28.75, 28.56, 26.01, 25.59, 24.22, 21.37, 19.45.

  Example 18: (+/-)-trans-3-((6- (dibenzo [b, d] furan-4-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (dibenzo [b, d] furan-4-yl) pyrimidine 2,4,6-Trichloropyrimidine (500 mg, 2.73 mmol) in 1,2-dimethoxyethane (32 mL) ) To a solution of tetrakis (triphenylphosphine) palladium (316 mg, 0.27 mmol), dibenzo [b, d] furan-4-ylboronic acid (583 mg, 2.75 mmol) and aqueous sodium carbonate (1M, 8.18 mL, 8.18 mmol) was added. The mixture was stirred at 80 ° C. for 2 h. Water (30 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (550 mg, 31%).
MS (ESI, pos.ion) m / z: 315.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.58 (s, 1H), 8.56-8.51 (m, 1H), 8.19-8.15 (m, 1H), 8 .04 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.57 (dt, J = 15.4, 4.4 Hz, 2H), 7. 46 (t, J = 7.5 Hz, 1H).

Step 2: 3-((2-Chloro-6- (dibenzo [b, d] furan-4-yl) pyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+ / −)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (418 mg, 2.28 mmol) and 2,4-dichloro-6- ( After dibenzo [b, d] furan-4-yl) pyrimidine (600 mg, 1.90 mmol) was dissolved in DMF (6 mL), potassium carbonate (789 mg, 5.71 mmol) was added. The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a white solid (586 mg, 67%).
MS (ESI, pos.ion) m / z: 462.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.45 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.55-7.38 (m, 5H), 5.54 (s, 1H), 4.46 (s, 1H), 3.72 (s, 3H), 2 .46 (d, J = 5.3 Hz, 1H), 2.10 (s, 1H), 2.03 (s, 1H), 1.94-1.67 (m, 8H).

Step 3: 3-((6- (Dibenzo [b, d] furan-4-yl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a microwave tube with 5-fluoro-3- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (237 mg, 0.29 mmol, 50%), 3-((2-chloro -6- (dibenzo [b, d] furan-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (110 mg, 0.24 mmol), potassium carbonate (98 mg , 0.71 mmol), Pd (dppf) Cl ₂ (38 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (91 mg, 53%).
MS (ESI, pos.ion) m / z: 716.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.81 (dd, J = 8.9, 2.7 Hz, 1H), 8.77 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.35 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 8.11 (d, J = 7.7 Hz, 1H), 8.04 ( d, J = 7.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 14.7, 9.1 Hz, 2H), 7.44 (d , J = 7.5 Hz, 1H), 7.39 (d, J = 4.3 Hz, 2H), 7.31 (s, 1H), 5.28 (s, 1H), 4.73 (d, J = 4.7 Hz, 1H), 3.73 (s, 3H), 2.52 (d, J = 5.7 Hz, 1H), 2.40 (s, 3H), 2.13 (s, 2H), 1.74 (m, 8H .

Step 4: (+/-)-trans-3-((6- (dibenzo [b, d] furan-4-yl) -2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (dibenzo) in THF / MeOH (v / v = 1/1, 2 mL) [B, d] furan-4-yl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (91 mg, 0.13 mmol) was added aqueous sodium hydroxide (4M, 0.33 mL, 1.30 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (45 mg, 65%).
MS (ESI, pos.ion) m / z: 548.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 548.2118 [M + H] ⁺ , (C ₃₂ H ₂₆ FN ₅ O ₃ ) [M + H] ⁺ Theoretical value: 548.2098;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.30 (s, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.52 (d, J = 7. 0 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J = 7.2 Hz, 2H), 8.25 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.73 (s, 1H), 7.62 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7. 43 (s, 1H), 4.71 (s, 1H), 2.58 (s, 1H), 1.93-1.37 (m, 10H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.04, 172.49, 163.00, 162.42, 156.90, 156.75, 155.86, 155.30, 153. 79, 146.50, 131.80, 131.72, 131.61, 128.44, 127.44, 125.15, 123.96, 123.92, 123.72, 123.22, 122.94, 121.79, 119.12, 119.06, 115.75, 115.11, 112.07, 102.42, 67.48, 50.65, 49.82, 29.49, 28.83, 28. 53, 26.07, 25.59, 24.25, 21.52, 21.45, 19.52.

  Example 19: (+/-)-cis-N- (3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) pyrrolidine-1-carboxamide

Step 1: N- (3 - (( 2- chloro-6-phenyl-pyrimidin-4-yl) amino) cyclohexyl) ^{pyrrolidin-1-N} 1 in carboxamide tetrahydrofuran (4 mL) - (2-chloro-6-phenylpyrimidine To a solution of -4-yl) cyclohexane-1,3-diamine (75 mg, 0.25 mmol), N, N-diisopropylethylamine (0.12 mL, 0.74 mmol) and pyrrolidine-1-carbonyl chloride (49 mg, 0. 37 mmol) was added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness in vacuo to give the title compound as a colorless solid (99 mg, 100%).
MS (ESI, pos.ion) m / z: 400.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.91 (s, 2H), 7.49 (d, J = 2.1 Hz, 3H), 6.75 (s, 1H), 96-1.85 (m, 5H), 1.42 (s, 1H), 1.25 (m, 8H).

Step 2: (+/-)-cis-N- (3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine -4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide In a microwave tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1-tosyl-1H-pyrrolo [2,3-b] pyridine (249 mg, 0.30 mmol, 50%), N- (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) pyrrolidin-1-carboxamide (100mg, 0.25mmol), potassium carbonate _{(103mg, 0.75mmol), Pd (} dppf) Cl 2 (40mg, 0.05mmol), 1,4 Dioxane was added (3 mL) and water (0.2 mL). The mixture in the microwave tube was stirred at 120 ° C. for 4 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (83 mg, 51%) .
MS (ESI, pos.ion) m / z: 654.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.66 (s, 1H), 8.29 (s, 1H), 8.09 (t, J = 7.5 Hz, 4H), 7. 52 (d, J = 7.5 Hz, 4H), 7.40 (d, J = 8.2 Hz, 2H), 6.77 (s, 1H), 5.88 (d, J = 7.9 Hz, 1H) ), 4.59 (s, 2H), 3.80 (s, 1H), 2.39 (s, 3H), 1.85-1.92 (m, 6H), 1.34 (m, 8H) .

Step 3: (+/-)-cis-N- (3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) pyrrolidine-1-carboxamide (+/-)-cis-N- (3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3- b] To a solution of pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide (83 mg, 0.13 mmol), a solution of sodium methoxide in methanol (5M, 0 .26 mL, 1.3 mmol) was added. The mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated in vacuo to dryness and water (10 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (32 mg, 50%).
MS (ESI, pos.ion) m / z: 500.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 500.2568 [M + H] ⁺ , (C ₂₈ H ₃ 1FN ₇ O) [M + H] ⁺ Theoretical value: 500.2574;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H) ), 8.11 (s, 2H), 7.55-7.50 (m, 3H), 7.36 (s, 1H), 6.76 (s, 1H), 5.84 (d, J = 7.9 Hz, 1H), 4.11 (s, 1H), 3.66 (d, J = 7.8 Hz, 1H), 3.19 (d, J = 6.4 Hz, 4H), 2.16 ( s, 2H), 1.80 (s, 6H), 1.53-1.24 (m, 4H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 162.78, 162.43, 156.85, 156.37, 155.26, 146.48, 138.46, 131.76, 131. 56, 130.28, 129.19, 126.77, 119.08, 119.03, 115.08, 56.50, 49.14, 48.61, 45.76, 33.01, 32.36, 29.43, 25.47, 25.42, 23.50, 22.54, 19.01.

  Example 20: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (furan-3-yl) pyrimidine To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in 1,2-dimethoxyethane (32 mL) was added tetrakis. (Triphenylphosphine) palladium (317 mg, 0.27 mmol), 3-furylboronic acid (308 mg, 2.75 mmol) and aqueous sodium carbonate (1M, 8.18 mL, 8.18 mmol) were added. The mixture was stirred at 80 ° C. for 1 h. Water (30 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (317 mg, 31%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.26 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 6.89 (s, 1H).

Step 2: 3-((2-Chloro-6- (furan-3-yl) pyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (324 mg, 1.77 mmol) and 2,4-dichloro-6- (furan-3-yl) After pyrimidine (317 mg, 1.47 mmol) was dissolved in DMF (6 mL), potassium carbonate (611 mg, 4.42 mmol) was added. The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a white solid (353 mg, 66%).
MS (ESI, pos.ion) m / z: 362.1 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl microwave tube with 5-fluoro-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (290 mg, 0.35 mmol, 50%), 3-((2-chloro-6- (furan- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (105 mg, 0.29 mmol), potassium carbonate (120 mg, 0. 85 mmol), Pd (dpp _{f) Cl 2 (47mg, 0.06mmol} ), was added 1,4-dioxane (3 mL) and water (0.2 mL). After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (179 mg, 100%).
MS (ESI, pos.ion) m / z: 616.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.66 (s, 1H), 8.63 (dd, J = 8.9, 2.7 Hz, 1H), 8.32 (s, 1H) 8.19 (s, 1H), 8.12 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 7.39 (d, J = 4.6 Hz, 2H), 7 .30 (s, 1H), 6.91 (s, 1H), 5.21 (s, 1H), 4.72 (s, 1H), 3.74 (s, 3H), 2.45-2. 42 (m, 1H), 2.39 (s, 3H), 2.10 (s, 1H), 1.96 (s, 1H), 1.81 (m, 8H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl) in THF / MeOH (v / v = 1/1, 4 mL) -1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( To a solution of +/−)-trans-methyl (180 mg, 0.29 mmol) was added aqueous sodium hydroxide (4M, 0.73 mL, 2.90 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (62 mg, 47%).
MS (ESI, pos.ion) m / z: 448.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 448.1785 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₇ O ₃ ) [M + H] ⁺ Theoretical: 448.1784;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.25 (s, 1 H), 8.62 (s, 1 H), 8.41 (s, 1 H), 8.35 (s, 1 H ), 8.27 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 6.98 (s, 1H), 6.48 (s, 1H), 4.63 (S, 1H), 3.17 (s, 1H), 1.99 (s, 2H), 1.88-1.44 (m, 8H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 175.99, 172.43, 162.82, 162.39, 157.27, 154.88, 144.46, 144.88, 143. 19, 131.75, 131.60, 131.46, 126.56, 119.05, 118.97, 116.07, 114.90, 108.96, 56.50, 50.48, 49.74, 49.05, 28.78, 28.60, 25.99, 24.13, 21.50, 21.40, 19.41.

  Example 21: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine -4-yl) amino) cyclohexyl) thiazole-4-carboxamide

Step 1: 2-amino-N- (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide
To a solution of N ^1- (2-chloro-6-phenylpyrimidin-4-yl) cyclohexane-1,3-diamine (63 mg, 0.21 mmol) in a mixed solvent of tetrahydrofuran (4 mL) and dimethyl sulfoxide (1 mL), N, N-diisopropylethylamine (0.08 mL, 0.62 mmol) and 2-aminothiazole-4-carboxylic acid (59 mg, 0.42 mmol) were added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a white solid (89 mg, 100%).
MS (ESI, pos.ion) m / z: 429.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.92 (s, 2H), 7.49 (s, 3H), 7.26 (s, 1H), 6.77 (s, 1H) 4.59 (s, 1H), 2.68 (s, 1H), 2.32 (d, J = 11.1 Hz, 1H), 2.11-1.90 (m, 4H), 1.59 (D, J = 13.1 Hz, 1H).

Step 2: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl)- 6-Phenylpyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide In a microwave tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (209 mg, 0.25 mmol, 50%), (+/-)-cis-2-amino-N- (3-((2 -Chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide (90 mg, 0.21 mmol), potassium phosphate (133 mg, 0.63 mmol), Pd ₂ (dba) ₃ (20 mg, 0.02 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 hours under microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (43 mg, 30%) .

Step 3: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine -4-yl) amino) cyclohexyl) thiazole-4-carboxamide (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1-tosyl-) in methanol (1 mL) To a solution of 1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide (43 mg, 0.06 mmol) was added sodium in methanol. A solution of methoxide (5M, 0.12 mL, 0.6 mmol) was added. The mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated in vacuo and water (10 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (32 mg, 50 %).
MS (ESI, pos.ion) m / z: 529.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 529.1940 [M + H] ⁺ , (C ₂₇ H ₂₆ FN ₈ OS) [M + H] ⁺ Theoretical: 529.1934;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H) ), 8.11 (s, 2H), 7.58-7.48 (m, 4H), 7.38 (s, 1H), 7.18 (s, 1H), 7.08 (s, 2H) 6.77 (s, 1H), 4.12 (s, 1H), 3.94 (s, 1H), 1.86 (s, 2H), 1.44 (m, 6H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 168.62, 162.43, 160.44, 156.86, 155.27, 146.48, 146.21, 138.44, 131. 77, 131.58, 130.31, 130.12, 129.20, 126.80, 119.07, 119.02, 115.10, 111.69, 48.86, 32.08, 31.75, 30.86, 29.47, 29.15, 22.55, 14.42.

  Example 22: (+/-)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide

Step 1: (+/-)-cis-N- (3-((2-chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide tetrahydrofuran (4 mL ) And dimethyl sulfoxide (1 mL) in a solution of N ^1- (2-chloro-6-phenylpyrimidin-4-yl) cyclohexane-1,3-diamine (221 mg, 0.73 mmol) in N, N -Diisopropylethylamine (0.11 mL, 0.7 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (184 mg, 1.46 mmol) were added. The mixture was stirred at rt for 10 min before HATU (555 mg, 1.46 mmol) was added. The resulting mixture was stirred at rt for 3 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (180 mg, 60%).
MS (ESI, pos.ion) m / z: 411.2 [M + H] ^< +>.

Step 2: (+/-)-cis-N- (3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine -4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide In a microwave tube, 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (162 mg, 0.23 mmol, 60%), (+/−)-cis-N- (3-((2- Chloro-6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide (80 mg, 0.19 mmol), potassium carbonate (80 mg, 0.58 mmol), Pd _{(Dppf) Cl 2 (31mg,} 0.04mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (20 mg, 15%).
MS (ESI, pos.ion) m / z: 665.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.73 (d, J = 3.2 Hz, 1H), 8.68 (s, 1H), 8.40 (d, J = 8.7 Hz) , 1H), 8.29 (s, 1H), 8.10 (d, J = 8.2 Hz, 4H), 7.63 (s, 2H), 7.53 (d, J = 7.5 Hz, 2H) ), 7.39 (d, J = 7.9 Hz, 2H), 6.79 (s, 1H), 4.10 (s, 1H), 3.77 (s, 3H), 2.45 (s, 1H), 2.39 (s, 3H), 2.27-2.17 (m, 2H), 2.10-1.97 (m, 4H), 1.62 (s, 2H).

Step 3: (+/-)-cis-N- (3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl ) Amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide (+/-)-cis-N- (3-((2- (5-fluoro-1-tosyl-1H) in methanol (1 mL) A solution of -pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide (20 mg, 0.03 mmol) To was added a solution of sodium methoxide in methanol (5M, 0.06 mL, 0.3 mmol). The mixture was stirred at 30 ° C. overnight. The reaction mixture was concentrated in vacuo and water (10 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (10 mg, 65 %).
HRMS (ESI, pos.ion) m / z: 51.2385 [M + H] ⁺ , (C ₂₈ H ₂₈ FN ₈ O) [M + H] ⁺ Theoretical value: 511.2370;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1 H), 8.59 (s, 1 H), 8.40 (s, 1 H), 8.29 (s, 1 H ), 8.11 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.57-7. 50 (m, 2H), 7.37 (s, 1H), 6.75 (s, 1H), 4.14 (s, 1H), 3.68 (s, 3H), 2.20 (s, 2H) ), 1.84 (s, 2H), 1.55-1.33 (m, 4H).

  Example 23: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (thiophen-2-yl) pyrimidine To a solution of thiophene (500 mg, 5.94 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium (2.4 mL, 6.0 mmol). 2.5 mol / L) at −15 ° C. and the mixture was stirred at −15 ° C. for 1 h. Then ZnCl-TMEDA (495 mg, 1.96 mmol) was added to the mixture and the resulting mixture was stirred for 1 h. Then palladium dichloride (105 mg, 0.59 mmol), triphenylphosphine (658 mg, 1.19 mmol) and 2,4,6-trichloropyrimidine (1.09 g, 5.94 mmol) were added in turn to the mixture. The resulting mixture was heated to 55 ° C. under nitrogen protection and then stirred at this temperature overnight. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (616 mg, 45%).
MS (ESI, pos.ion) m / z: 230.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.86 (d, J = 3.7 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.51 (s, 1H), 7.24-7.17 (m, 1H).

Step 2: 3-((2-Chloro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (586 mg, 3.20 mmol) and 2,4-dichloro-6- (thiophen-2-yl) After pyrimidine (616 mg, 2.67 mmol) was dissolved in DMF (6 mL), potassium carbonate (1.11 g, 8.00 mmol) was added. The mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (180 mg, 18%).
MS (ESI, pos.ion) m / z: 378.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.74 (d, J = 3.1 Hz, 1H), 7.50 (d, J = 4.9 Hz, 1H), 7.17-7. 10 (m, 1H), 6.68 (s, 1H), 5.47 (s, 1H), 4.30 (s, 1H), 3.76 (s, 3H), 2.39 (d, J = 4.6 Hz, 1H), 2.08 (s, 1H), 1.87 (d, J = 2.5 Hz, 1H), 1.82-1.65 (m, 8H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl microwave tube with 5-fluoro-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (176 mg, 0.25 mmol, 60%), 3-((2-chloro-6- (thiophene- 2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate methyl (80 mg, 0.21 mmol), potassium carbonate (87 mg, 0.64 mmol), Pd (dppf) Cl ₂ (34 g, 0.04 mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 h while being heated by microwave. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (40 mg, 30%) .
MS (ESI, pos.ion) m / z: 632.3 [M + H] ^< +>.

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl) in THF / MeOH (v / v = 1/1, 2 mL) -1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( To a solution of +/−)-trans-methyl (40 mg, 0.06 mmol) was added aqueous sodium hydroxide (4M, 0.15 mL, 0.60 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (20 mg, 68%).
MS (ESI, pos.ion) m / z: 464.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 464.1526 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₂ S) [M + H] ⁺ Theoretical: 464.1556;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.67 (s, 1H), 8.29 (s, 2H), 7.73 (d, J = 4.8 Hz, 2H), 7.48 (s, 1H), 7.26-7.17 (m, 1H), 6.68 (s, 1H), 4.58 (s, 1H), 1. 98-1.91 (m, 2H), 1.84-1.38 (m, 8H).

  Example 24: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-6- (5-nitrofuran-2-yl) pyrimidine To concentrated sulfuric acid (10 mL), 2,4-dichloro-6- (furan-2-yl) pyrimidine (2.15 g, 10.00 mmol) was added. After the mixture was placed in an ice bath and stirred, concentrated nitric acid (0.85 mL, 12 mmol) was slowly added dropwise to the mixture. The resulting mixture was then heated to room temperature and continuously stirred. The reaction was stopped and the reaction mixture was slowly added dropwise to ice water (50 mL) to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow powder (1.02 g, 39%) .
MS (ESI, pos.ion) m / z: 260.10 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.81 (s, 1H), 7.57 (d, J = 3.8 Hz, 1H), 7.48 (d, J = 3.8 Hz, 1H) ).

Step 2: 3-((2-Chloro-6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+/-) 2,4-Dichloro-6- (5-nitrofuran-2-yl) pyrimidine (300 mg, 1.15 mmol), 3-aminobicyclo [2.2.2] octane in trans-methyl DMF (10 mL) A suspension of 2-carboxylic acid (+/−)-trans-methyl (280 mg, 1.38 mmol) and K ₂ CO ₃ (320 mg, 2.31 mmol) was stirred at rt overnight. The reaction was quenched with water (100 mL) and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (344 mg, 73%).
MS (ESI, pos.ion) m / z: 407.20 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.42 (d, J = 3.7 Hz, 1H), 7.36 (d, J = 3.2 Hz, 1H), 6.89 (s, 1H), 4.33 (s, 1H), 3.80 (s, 3H), 2.40 (d, J = 4.4 Hz, 1H), 2.06 (s, 1H), 1.87 (s) , 1H), 1.81-1.56 (m, 9H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (170 mg, 0.41 mmol), K ₂ CO ₃ (154 mg, 1. 11 mmol), PdCl ₂ (dppf) (30 mg, 0.04 mmol) and 3-((2-chloro-6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2. 2] Octane-2-cal Boronic acid (+/−)-trans-methyl (150 mg, 0.37 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was sealed in a tube and stirred at 115 ° C. for 3 h. The mixture was filtered to remove solid impurities and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (126 mg, 52%).
MS (ESI, pos.ion) m / z: 661.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.70 (s, 1H), 8.59 (dd, J = 8.8, 2.7 Hz, 1H), 8.34 (d, J = 1) .7 Hz, 1H), 8.15 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 3.8 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H) 7.31 (d, J = 8.2 Hz, 2H), 6.85 (s, 1H), 5.37 (s, 1H), 3.78 (s, 3H), 2.44 (s, 1H) ), 2.40 (s, 3H), 2.13 (s, 1H), 2.07 (s, 1H), 2.00 (s, 1H), 1.75-1.61 (m, 8H) .

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl Hydrogen chloride solution in 1,4-dioxane (4 mol / L, 0.20 mL) was added to 3-((2 -(5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] Octane-2-carboxylic acid (+/−)-trans-methyl (43 mg, 0.07 mmol) was added and the mixture was stirred at 55 ° C. The reaction was stopped and the reaction mixture was concentrated in vacuo to remove the solvent and HCl to give a pale yellow solid (32 mg, 97%). It was used in the next step without further purification.
MS (ESI, pos.ion) m / z: 507.30 [M + H] ^< +>.

Step 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1H-pyrrolo [2,3-b]) in THF (5 mL) Pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl To a solution of (20 mg, 0.04 mmol) was added a solution of LiOH (5 mg, 0.16 mmol) in water (0.5 mL). The mixture was stirred at 50 ° C. overnight and then acidified to pH ˜6 with hydrochloric acid (1M). The resulting mixture was extracted with 2-methyltetrahydrofuran (15 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (6 mg, 31%).
MS (ESI, pos.ion) m / z: 493.20 [M + H] ⁺ ;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 12.36 (s, 1 H), 8.60 (d, J = 9.0 Hz, 1 H), 8.41 (s, 1 H), 8. 30 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 6.5 Hz, 1H), 7.59 (s, 1H), 6.86 (s, 1H), 5 .33 (s, 1H), 4.64 (s, 1H), 2.03-1.96 (m, 2H), 1.61 (m, 9H).

  Example 24a: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -Ethyl The title compound was 2,4-dichloro-6- (5-nitrofuran-2-yl) pyrimidine (300 mg, 1.15 mmol), 3-aminobicyclo [2.2.2] octane-2 as a reagent. As described in Step 2 of Example 24 using carboxylic acid (2S, 3S) -ethyl hydrochloride (328 mg, 1.40 mmol), potassium carbonate (477 mg, 3.45 mmol) and DMF (10 mL) as solvent. It can be prepared by synthetic methods. The title compound was a white solid (271 mg, 56%).
MS (ESI, pos.ion) m / z: 421.1 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 5-fluoro-3- (4,4,5,5-tetramethyl as a reagent. -1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (298 mg, 0.43 mmol, 60%), K ₂ CO ₃ (155 mg, 1.11 mmol) ), Pd (dppf) Cl ₂ (29 mg, 0.04 mmol) and 3-((2-chloro-6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2. 2] Octane-2-carbo As described in Step 3 of Example 24 using acid (2S, 3S) -ethyl (148 mg, 0.35 mmol) and a mixture of 1,4-dioxane (8 mL) and H ₂ O (1 mL) as mixed solvent. It can be prepared by the synthesis method. The title compound was a white solid (125 mg, 53%).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl The title compound is 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3- b] Pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (125 mg, 0.19 mmol) and a solution of HCl in 1,4-dioxane (4 mol / L, 0.50 mL) can be prepared by the synthetic method described in Step 24 of Example 24. The title compound was a pale yellow solid (95 mg, 99%). This was used in the next step without further purification.
MS (ESI, pos.ion) m / z: 521.1 [M + H] ^< +>.

Step 5: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (5-nitrofuran-2-yl) pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid The title compound is 3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3 -Yl) -6- (5-nitrofuran-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (95 mg, 0. 0). 18 mmol), a solution of LiOH (17 mg, 0.72 mmol) in water (0.5 mL) and the solvent THF (5 mL) can be prepared by the synthetic method described in Step 5 of Example 24. The title compound was a white solid (27 mg, 30%).
HRMS (ESI, pos.ion) m / z: 493.1638 [M + H] ⁺ , (C ₂₄ H ₂₂ FN ₆ O ₅ ) [M + H] ⁺ Theoretical: 493.1636;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.35 (s, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.40 (s, 1H), 8 .30 (s, 1H), 7.86 (d, J = 3.7 Hz, 1H), 7.80 (d, J = 6.7 Hz, 1H), 7.57 (d, J = 3.2 Hz, 1H), 6.85 (s, 1H), 4.64 (s, 1H), 2.44 (s, 1H), 1.99 (s, 1H), 1.96 (s, 1H), 1. 77-1.39 (m, 8H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 175.82, 162.93, 162.64, 154.77, 152.13, 150.63, 146.48, 132.19, 131. 96, 131.71, 118.94, 115.82, 115.10, 113.30, 110.03, 98.24, 50.58, 50.03, 28.69, 28.41, 25.98, 24.15, 21.28, 19.36.

  Example 25: (+/−)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine in DMF (5 mL) (500 mg, 2.66 mmol) was added NaH (130 mg, 3.19 mmol, 60%) at 0 ° C. and the mixture was stirred at this temperature for 30 min. 2-Iodopropane (904 mg, 5.32 mmol) was then added to the mixture and the resulting mixture was stirred at rt overnight. The reaction was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (356 mg, 58%).
MS (ESI, pos.ion) m / z: 231.05 [M + H] ^< +>.

Step 2: 3-((2-Chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (390 mg, 1.96 mmol) and 2,4-dichloro-7-isopropyl- 7H-pyrrolo [2,3-d] pyrimidine (410 mg, 1.78 mmol) was dissolved in tetrahydrofuran (5 mL), and then potassium carbonate (493 mg, 3.56 mmol) was added. The mixture was stirred at rt overnight. The reaction was stopped and water (50 mL) was added to the reaction mixture to quench the reaction. The resulting mixture was partitioned and the aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (333 mg, 50%).
MS (ESI, pos.ion) m / z: 425.15 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39 (d, J = 4.2 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.43 (s, 1H), 5.25 (s, 1H), 5.04 (dt, J = 13.5, 6.8 Hz, 1H), 4.62 (s, 1H), 3.76 (s, 3H), 2 .42 (d, J = 5.4 Hz, 1H), 2.02 (s, 1H), 1.95 (d, J = 2.3 Hz, 1H), 1.88-1.74 (m, 2H) 1.69-1.62 (m, 5H), 1.45-1.49 (m, 6H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (200 mg, 0.48 mmol), K ₂ CO ₃ (166 mg, 1.19 mmol), Pd (dppf) Cl ₂ (32 mg, 0.04 mmol) and 3-((2-chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) Amino) bicyclo [2. 2.2] octane-2-carboxylic acid (+/-) - trans - mixture of methyl (150 mg, 0.40 _mmol), was added H 2 O (1 mL). Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture in the tube was sealed and stirred at 110 ° C. for 1.5 h. After the reaction was complete, the mixture was filtered to remove solid impurities. The filtrate was then concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give a white solid (124 mg, 49%).

Step 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of sodium hydroxide (78 mg, 1.97 mmol) in water (1 mL) was added to THF / MeOH (v / V = 5 mL / 5 mL) in 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2 , 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (124 mg, 0.20 mmol) was added. The reaction mixture is r.p. Stir at t overnight. Water (10 mL) was added. The reaction mixture was adjusted to pH ˜6 with hydrochloric acid (1M). The resulting mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (38 mg, 42%).
MS (ESI, pos.ion) m / z: 463.55 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 463.2262 [M + H] ⁺ , (C25H ₂₈ FN ₇ O ₂ ) [M + H] ⁺ Theoretical: 463.2258;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.08 (s, 1 H), 8.68 (d, J = 8.8 Hz, 1 H), 8.31-8.18 (m, 2H), 7.21 (d, J = 2.5 Hz, 2H), 6.64 (s, 1H), 5.08-4.96 (m, 1H), 4.79 (s, 1H), 2 .72 (d, J = 6.3 Hz, 1H), 2.03 (d, J = 12.3 Hz, 2H), 1.88-1.69 (m, 3H), 1.68-1.53 ( m, 3H), 1.49 (dd, J = 6.3, 3.3 Hz, 6H), 1.38 (d, J = 10.9 Hz, 2H), 1.19 (m, 1H).

  Example 26: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methyl-5H-pyrrolo [3,2 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-5-methyl-5H-pyrrolo [3,2-d] pyrimidine 2,4-Dichloro-5H-pyrrolo [3,2-d] pyrimidine in DMF (8 mL) (500 mg, 2.66 mmol) solution was added NaH (127 mg, 3.19 mmol, 60%) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 min before iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (275 mg, 51%).
MS (ESI, pos.ion) m / z: 202.00 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.47 (d, J = 3.1 Hz, 1H), 6.64 (d, J = 3.0 Hz, 1H), 4.16 (s, 3H).

Step 2: 3-((2-Chloro-5-methyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (236 mg, 1.17 mmol) and 2,4- in THF (5 mL) dichloro-5-methyl--5H- pyrrolo [3,2-d] pyrimidine (301 mg, 2.13 mmol) to a solution of _was added _{K 2 CO 3 (301mg, 2.16mmol} ). The mixture was then stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2) and the combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (122 mg, 33%).
MS (ESI, pos.ion) m / z: 350.15 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methyl-5H-pyrrolo [3,2-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (153 mg, 0.43 mmol), K ₂ CO ₃ (156 mg, 1.13 mmol), Pd (dppf) Cl ₂ (28 mg, 0.04 mmol) and 3-((2-chloro-5-methyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) Amino) bicyclo [2.2.2] oct To a mixture of tan-2-carboxylic acid (+/−)-trans-methyl (136 mg, 0.39 mmol) was added H ₂ O (1 mL). After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 110 ° C. for 1.5 h with microwave heating. The reaction mixture was filtered through a celite pad to remove solid impurities and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (75 mg, 32%).
MS (ESI, pos.ion) m / z: 604.40 [M + H] ^< +>.

Step 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methyl-5H-pyrrolo [3,2 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of sodium hydroxide (51 mg, 1.24 mmol) in water (1 mL) was added to THF / MeOH (v / V = 5 mL / 5 mL) in 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-methyl-5H-pyrrolo [3 , 2-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (75 mg, 0.12 mmol) was added. The reaction mixture was stirred at rt overnight. Water (10 mL) was added. The mixture was adjusted to pH about 6 with aqueous hydrochloric acid (1M). The resulting mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (21 mg, 39%) .
MS (ESI, pos.ion) m / z: 435.20 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 435.1944 [M + H] ⁺ , (C ₂₃ H ₂₄ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 435.1945;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.72 (s, 1H), 8.65-8.56 (m, 2H), 8.38 (s, 1H), 7.64 (S, 1H), 7.11 (s, 1H), 6.47 (d, J = 2.6 Hz, 1H), 5.14 (s, 1H), 4.15 (s, 3H), 2. 08 (s, 1H), 2.03 (s, 1H), 1.83 (d, J = 8.2 Hz, 3H), 1.58-1.48 (m, 5H).

  Example 27: (+/−)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-phenyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-7-phenyl-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine (300 mg, in DCM (5 mL)) To a solution of 1.60 mmol) was added phenylboronic acid (215 mg, 1.76 mmol), Cu (OAc) ₂ (580 mg, 3.19 mmol) and Et ₃ N (1.61 g, 15.95 mmol). The mixture was stirred at rt overnight in an oxygen atmosphere. Water (50 mL) was added to quench the reaction and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (296 mg, 70%).
MS (ESI, pos.ion) m / z: 265.35 [M + H] ^< +>.

Step 2: 3-((2-Chloro-7-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (245 mg, 1.23 mmol) and 2,4-dichloro-7-phenyl- 7H-pyrrolo [2,3-d] pyrimidine (296 mg, 1.12 mmol) was dissolved in DMF (10 mL), and then potassium carbonate (310 mg, 2.24 mmol) was added. The mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture to quench the reaction and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (156 mg, 34%).
MS (ESI, pos.ion) m / z: 412.15 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-phenyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4,4). 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (185 mg, 0.42 mmol), K ₂ CO ₃ (160 mg, 1.14 mmol), PdCl ₂ (dppf) (30 mg, 0.04 mmol) and 3-((2-chloro-7-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicycle [ 2.2.2] Octa 2-carboxylic acid (+/−)-trans-methyl (156 mg, 0.38 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was sealed in a tube and stirred at 110 ° C. for 1.5 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (135 mg, 53% ).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-phenyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-) in THF / MeOH (v / v = 5 mL / 5 mL) 1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2 To a solution of octane-2-carboxylic acid (+/−)-trans-methyl (120 mg, 0.18 mmol) was added a solution of sodium hydroxide (78 mg, 1.81 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified to pH ˜6 with hydrochloric acid (1M). The mixture was extracted with ethyl acetate (15 mL × 3) and the combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (61 mg, 68% ).
MS (ESI, pos.ion) m / z: 497.15 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 497.2106 [M + H] ⁺ , (C ₂₈ H ₂₆ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 497.2101;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.12 (s, 1 H), 8.62 (d, J = 8.1 Hz, 1 H), 8.26 (s, 1 H), 8 .22 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.60 (t, J = 7.8 Hz, 2H), 7.52 (d, J = 3.4 Hz, 1H), 7.45-7.38 (m, 2H), 6.90 (s, 1H), 4.81 (s, 1H), 2.74 (d, J = 6. 3 Hz, 1H), 2.04 (d, J = 15.2 Hz, 2H), 1.87-1.73 (m, 3H), 1.67-1.55 (m, 3H), 1.49- 1.39 (m, 3H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.15, 156.76, 156.24, 155.12, 150.20, 146.42, 138.64, 131.65, 131. 44, 130.44, 129.64, 126.48, 123.68, 123.25, 118.99, 118.86, 115.71, 101.44, 50.64, 49.04, 28.93, 28.81, 26.05, 24.25, 21.55, 19.53.

  Example 28: (+/-)-trans-3-((7-cyclopropyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-7-cyclopropyl-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine (500 mg in DMF (5 mL)) To a solution of 2.66 mmol), NaH (130 mg, 3.25 mmol, 60%) was added at 0 ° C. and the mixture was stirred at this temperature for 30 min. Cyclopropyl bromide (643 mg, 5.32 mmol) and cuprous iodide (3.19 g, 16.7 mmol) were then added to the mixture and the resulting mixture was stirred at 120 ° C. overnight. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (453 mg, 75%).
MS (ESI, pos.ion) m / z: 229.10 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.25 (d, J = 3.6 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 6.00 (ddd, J = 16.2, 10.9, 5.8 Hz, 1H), 5.31 (d, J = 10.2 Hz, 1H), 5.19 (d, J = 17.1 Hz, 1H), 4.87 (D, J = 5.7 Hz, 2H).

Step 2: 3-((2-Chloro-7-cyclopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / −)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (360 mg, 1.80 mmol) and 2,4-dichloro-7-cyclo Propyl-7H-pyrrolo [2,3-d] pyrimidine (374 mg, 1.64 mmol) was dissolved in DMF (5 mL) and then potassium carbonate (453 mg, 3.28 mmol) was added. The mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture to quench the reaction and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (370 mg, 60%).
MS (ESI, pos.ion) m / z: 376.15 [M + H] ^< +>.

Step 3: 3-((7-cyclopropyl-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (172 mg, 0.41 mmol), K ₂ CO ₃ (156 mg , 1.39 mmol), Pd (dppf) Cl ₂ (28 mg, 0.05 mmol) and 3-((2-chloro-7-cyclopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino ) Bicycle [2.2 .2] Octane-2-carboxylic acid (+/-)-trans-methyl (174 mg, 0.46 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 1.5 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (120 mg, 41%).

Step 4: (+/-)-trans-3-((7-cyclopropyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((7-cyclopropyl-2) in THF / MeOH (v / v = 5 mL / 5 mL) -(5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2 .2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (120 mg, 0.19 mmol) was added a solution of NaOH (78 mg, 1.91 mmol) in water (1 mL). The mixture was stirred at rt overnight and then acidified to pH ˜6 with dilute hydrochloric acid (1M). The resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (43 mg, 49%).
MS (ESI, pos.ion) m / z: 461.15 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 461.2113 [M + H] ⁺ , (C25H ₂₆ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 461.2101;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.17 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.28 (s, 2H), 7 .45 (s, 1H), 7.09 (s, 1H), 6.71 (s, 1H), 6.07 (s, 1H), 5.19 (d, J = 9.3 Hz, 1H), 5.08 (d, J = 16.9 Hz, 1H), 4.87 (s, 2H), 2.72 (s, 2H), 2.02 (s, 2H), 1.87-1.73 ( m, 3H), 1.48-1.40 (m, 5H).

  Example 29: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-phenyl-5H-pyrrolo [3,2 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-5-phenyl-5H-pyrrolo [3,2-d] pyrimidine 2,4-Dichloro-5H-pyrrolo [3,2-d] pyrimidine in DCM (5 mL) (1. To a solution of 00 g, 5.26 mmol) phenylboronic acid (710 mg, 5.79 mmol), cupric acetate (1.82 g, 10.52 mmol), Et ₃ N (5.32 g, 53.62 mmol) were added. . The reaction mixture was then stirred at rt overnight under an oxygen atmosphere. Water (50 mL) was added to quench the reaction and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (1.03 g, 74%).
MS (ESI, pos.ion) m / z: 265.20 [M] +.

Step 2: 3-((2-Chloro-5-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (267 mg, 1.3 mmol) in THF (5 mL), 2,4- dichloro-5-phenyl--5H- pyrrolo [3,2-d] pyrimidine (322 mg, 1.22 mmol) to a solution of _was added _{K 2 CO 3 (337mg, 2.44mmol} ). The mixture was then stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2) and the combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (150 mg, 30%).
MS (ESI, pos.ion) m / z: 411.10 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-phenyl-5H-pyrrolo [3,2-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (150 mg, 0.36 mmol), K ₂ CO ₃ (140 mg, 0.99 mmol), Pd (dppf) Cl ₂ (25 mg, 0.02 mmol) and 3-((2-chloro-5-phenyl-5H-pyrrolo [3,2-d] pyrimidin-4-yl) Amino) bicyclo [2.2.2] To a mixture of octane-2-carboxylic acid (+/−)-trans-methyl (136 mg, 0.33 mmol) was added water (1 mL). After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 110 ° C. for 1.5 h with microwave heating. The reaction mixture was filtered through a celite pad to remove solid impurities and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (185 mg, 84%).

Step 4: (+/-)-Trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-phenyl-5H-pyrrolo [3,2 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of NaOH (123 mg, 2.78 mmol) in water (1 mL) was added to THF / MeOH (v / v = 5 mL / 5 mL) in 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -5-phenyl-5H-pyrrolo [3,2 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (185 mg, 0.28 mmol) was added. The reaction mixture was stirred at rt overnight. Water (10 mL) was added and the resulting mixture was adjusted to pH ˜6 with aqueous hydrochloric acid (1M). The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (63 mg, 46% ).
MS (ESI, pos.ion) m / z: 497.10 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 497.2094 [M + H] ⁺ , (C ₂₈ H ₂₆ FN ₇ O ₂ ) [M + H] ⁺ Theoretical value: 497.2101;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 8.69 (dd, J = 9.8, 2.7 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.66-7.61 (m, 3H) ), 7.59 (d, J = 7.6 Hz, 3H), 6.66 (d, J = 3.1 Hz, 1H), 4.74 (s, 1H), 2.03 (s, 1H), 1.88 (d, J = 2.4 Hz, 1H), 1.83 (s, 1H), 1.68 (d, J = 9.2 Hz, 1H), 1.53 (m, 4H), 1. 34 (m, 4H).

  Example 30: (+/-)-Trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 2,4-Dichloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine in DMF (5 mL) (500 mg, 2.66 mmol) was added NaH (120 mg, 2.93 mmol, 60%) at 0 ° C. and the mixture was stirred at this temperature for 30 min. Paratoluenesulfonyl chloride (608 mg, 3.19 mmol) was then added to the mixture and the resulting mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture to quench the reaction and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (780 mg, 86%).
MS (ESI, pos.ion) m / z: 343.90 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.13 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 4.0 Hz, 1H), 2.45 (s, 3H).

Step 2: 3-((2-Chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (500 mg, 2.51 mmol) and 2,4-dichloro-7-tosyl- After 7H-pyrrolo [2,3-d] pyrimidine (780 mg, 2.28 mmol) was dissolved in DMF (10 mL), potassium carbonate (630 mg, 4.56 mmol) was added. The mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (803 mg, 72%).
MS (ESI, pos.ion) m / z: 490.50 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.09 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 3.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.48 (s, 1H), 4.52 (t, J = 5.8 Hz, 1H), 3.73 (s, 3H), 2.42 (s, 3H) 1.99 (s, 1H), 1.86 (s, 1H), 1.73 (s, 2H), 1.70-1.37 (m, 9H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (187 mg, 0.45 mmol), K ₂ CO ₃ (170 mg, 1.23 mmol), Pd (dppf) Cl ₂ (30 mg, 0.04 mmol) and 3-((2-chloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) Amino) bicyclo [2.2.2] oct To a mixture of tan-2-carboxylic acid (+/−)-trans-methyl (200 mg, 0.41 mmol) was added water (1 mL). The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 1.5 h. The reaction mixture was filtered through a celite pad to remove solid impurities and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (292 mg, 96%).

Step 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of NaOH (120 mg, 2.84 mmol) in water (1 mL) was added to THF / MeOH (v / v = 5 mL / 5 mL). 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-tosyl-7H-pyrrolo [2,3-d] pyrimidine) -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (212 mg, 0.28 mmol) was added. The reaction mixture was stirred at rt overnight. Water (10 mL) was added and the reaction mixture was adjusted to pH ˜6 with aqueous hydrochloric acid (1M) solution. The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (51 mg, 43% ).
MS (ESI, pos.ion) m / z: 421.10 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 421.1800 [M + H] ⁺ , (C ₂₂ H ₂₃ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 421.1788;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.04 (s, 1H), 11.32 (s, 1H), 8.73 (d, J = 10.2 Hz, 1H), 8 .25 (s, 1H), 8.15 (s, 1H), 7.19 (d, J = 6.5 Hz, 1H), 7.03 (s, 1H), 6.61 (s, 1H), 4.80 (s, 1H), 2.73 (d, J = 6.1 Hz, 1H), 2.02 (s, 1H), 1.93-1.33 (m, 7H), 1.23 ( s, 2H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.16, 156.73, 155.99, 155.07, 146.29, 131.48, 131.23, 130.08, 129. 91, 129.48, 120.66, 119.06, 115.95, 100.99, 99.44, 50.45, 48.94, 29.01, 28.87, 26.00, 24.14, 21.53, 19.43.

  Example 31: (+/-)-trans-3-((6- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3,4] -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 4,6-Dichloro-1-methyl-1H-pyrazolo [3,4-d] pyrimidine 4,6-Dichloro-1H-pyrazolo [3,4-d] pyrimidine (110 mg, in DMF (8 mL)) To a solution of 0.58 mmol) was added K ₂ CO ₃ (160 mg, 1.16 mmol). The reaction mixture was stirred at rt for 30 min and iodomethane (3.78 g, 26.60 mmol) was added. The reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction and the mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (48 mg, 41%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.16 (s, 1H), 4.13 (s, 3H).

Step 2: 3-((6-Chloro-1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (132 mg, 0.67 mmol) and 4,6- in THF (5 mL) To a solution of dichloro-1-methyl-1H-pyrazolo [3,4-d] pyrimidine (123 mg, 0.61 mmol) was added K ₂ CO ₃ (167 mg, 1.21 mmol). The mixture was then stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (201 mg, 95%).
MS (ESI, pos.ion) m / z: 351.10 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.00 (s, 1H), 4.62 (t, J = 6.3 Hz, 1H), 3.99 (s, 3H), 3.74 (S, 3H), 2.44 (s, 1H), 1.94 (s, 1H), 1.88-1.37 (m, 10H).

Step 3: 3-((6- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3,4-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (86 mg, 0.21 mmol), K ₂ CO ₃ (78 mg, 0.57 mmol), Pd (dppf) Cl ₂ (15 mg, 0.02 mmol) and 3-((6-chloro-1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) Amino) bicyclo [2.2.2] oct To a mixture of tan-2-carboxylic acid (+/−)-trans-methyl (66 mg, 0.19 mmol) was added water (1 mL). After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 110 ° C. for 1.5 h. The reaction mixture was filtered through a celite pad to remove solid impurities. The filtrate was then concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (53 mg, 47%).
MS (ESI, pos.ion) m / z: 605.10 [M + H] ^< +>.

Step 4: (+/-)-trans-3-((6- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3,4] -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of NaOH (41 mg, 0.94 mmol) in water (1 mL) was added to THF / MeOH (v / v = 5 mL / 5 mL) in 3-((6- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -1-methyl-1H-pyrazolo [3,4 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (57 mg, 0.09 mmol) was added. The reaction mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was adjusted to pH about 6 with aqueous hydrochloric acid (1M). The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (33 mg, 80%).
MS (ESI, pos.ion) m / z: 436.10 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 436. 1910 [M + H] ⁺ , (C ₂₂ H ₂₃ FN ₇ O ₂ ) [M + H] ⁺ Theoretical: 436.1897;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): ¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1 H), 8.68 (d, J = 9 .3 Hz, 1 H), 8.34 (s, 1 H), 8.28 (s, 1 H), 8.10 (s, 1 H), 7.99 (d, J = 6.4 Hz, 1 H), 83 (s, 1H), 3.96 (s, 3H), 2.67 (s, 1H), 2.03 (s, 2H), 1.84-1.41 (m, 9H).

  Example 32: (+/−)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-nonyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-7-nonyl-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine in DMF (5 mL) (500 mg, To a solution of 2.66 mmol) NaH (130 mg, 3.19 mmol) was added at 0 ° C. and the mixture was stirred at this temperature for 30 min. Bromononane (1.03 mg, 5.32 mmol) was then added to the mixture and the resulting mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (821 mg, 98%).
MS (ESI, pos.ion) m / z: 315.10 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.24 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 3.5 Hz, 1H), 4.23 (t, J = 7.3 Hz, 2H), 1.84 (dt, J = 14.1, 7.2 Hz, 2H), 1.31-1.23 (m, 12H), 0.87 (t, J = 7) .0Hz, 3H).

Step 2: 3-((2-Chloro-7-nonyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (572 mg, 2.87 mmol) and 2,4- in THF (5 mL) To a solution of dichloro-7-nonyl-7H-pyrrolo [2,3-d] pyrimidine (821 mg, 2.61 mmol) was added DIPEA (4.6 mL, 26.13 mmol). The mixture was then stirred overnight at room temperature. The reaction was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (174 mg, 14%).
MS (ESI, pos.ion) m / z: 462.15 [M + H] ^< +>.

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-nonyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4 in 1,4-dioxane (8.0 mL) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (172 mg, 0.42 mmol), K ₂ CO ₃ (156 mg, 1.13 mmol), Pd (dppf) Cl ₂ (28 mg, 0.04 mmol) and 3-((2-chloro-7-nonyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) Amino) bicyclo [2.2.2] oct To a mixture of tan-2-carboxylic acid (+/−)-trans-methyl (174 mg, 0.38 mmol) was added H ₂ O (1 mL) under a nitrogen atmosphere. After removing the gas in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 110 ° C. for 1.5 h with microwave heating. The reaction mixture was filtered through a celite pad to remove solid impurities. The filtrate was then concentrated in vacuo to remove the solvent. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (216 mg, 80%).

Step 4: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-nonyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of NaOH (79 mg, 1.58 mmol) in water (1 mL) was added to THF / MeOH (v / v = 5 mL / 5 mL) in 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-nonyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (113 mg, 0.16 mmol) was added. The reaction mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was adjusted to pH about 6 with aqueous hydrochloric acid (1M). The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (31 mg, 36%).
MS (ESI, pos.ion) m / z: 547.70 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 421.1800 [M + H] ⁺ , (C ₃₁ H ₄₀ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 421.1788;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.06 (s, 1H), 8.70 (dd, J = 9.8, 2.3 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.21 (d, J = 6.4 Hz, 1H), 7.06 ( d, J = 3.2 Hz, 1H), 6.62 (s, 1H), 4.78 (s, 1H), 4.16 (t, J = 6.6 Hz, 2H), 4.13-4. 09 (m, 1H), 2.71 (d, J = 6.7 Hz, 1H), 2.02 (d, J = 11.4 Hz, 2H), 1.89-1.71 (m, 5H), 1.58 (m, 4H), 1.37-1.17 (m, 12H), 0.74 (t, J = 6.6 Hz, 3H).

  Example 33: (+/−)-trans-3-((7-benzyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 7-Benzyl-2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-7H-pyrrolo [2,3-d] pyrimidine in DMF (5 mL) (500 mg, 2.66 mmol) was added NaH (130 mg, 3.19 mmol, 60%) at 0 ° C. and the mixture was stirred at this temperature for 30 min. Benzyl bromide (904 mg, 5.32 mmol) was then added to the mixture and the resulting mixture was stirred at rt overnight. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (683 mg, 92%).
MS (ESI, pos.ion) m / z: 279.30 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39-7.32 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.43 (s, 2H).

Step 2: 3-((7-Benzyl-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (236 mg, 1.19 mmol) and 2,4- in THF (5 mL) dichloro-7-nonyl -7H- pyrrolo [2,3-d] pyrimidine (300 mg, 1.08 mmol) to a solution of _was added _{K 2 CO 3 (301mg, 2.16mmol} ). The mixture was then stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and the resulting mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a white solid (250 mg, 55%).
MS (ESI, pos.ion) m / z: 425.15 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39-7.36 (m, 1H), 7.31 (dd, J = 11.7, 4.5 Hz, 3H), 7.20 ( d, J = 7.3 Hz, 2H), 6.90-6.79 (m, 1H), 6.42 (s, 1H), 5.33 (d, J = 8.4 Hz, 2H), 4. 60 (d, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.43 (d, J = 5.2 Hz, 1H), 2.06 (s, 1H), 2.02 ( s, 1H), 1.94 (d, J = 2.3 Hz, 1H), 1.71 (m, 8H).

Step 3: 3-((7-Benzyl-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4,4). 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (172 mg, 0.41 mmol), K ₂ CO ₃ (156 mg, 1.13 mmol), PdCl ₂ (dppf) (28 mg, 0.04 mmol) and 3-((7-benzyl-2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octa 2-carboxylic acid (+/−)-trans-methyl (174 mg, 0.38 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 1.5 h. The mixture was filtered through a celite pad to remove solid impurities, the filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) The title compound was obtained as a white solid (89 mg, 32%).

Step 4: (+/-)-trans-3-((7-benzyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid A solution of NaOH (56 mg, 1.31 mmol) in water (1 mL) was added to THF / MeOH (v / v = 5 mL / 5 mL) in 3-((7-benzyl-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (89 mg, 0.13 mmol) was added. The reaction mixture is r.p. t. And stirred overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was adjusted to pH ˜6 with aqueous HCl (1M). The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (20 mg, 30%).
MS (ESI, pos.ion) m / z: 511.60 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 51.2257 [M + H] ⁺ , (C ₂₉ H ₂₈ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 511.2258;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.09 (s, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.28-8.21 (m, 2H), 7.72-7.66 (m, 4H), 7.31 (s, 2H), 7.17 (d, J = 3.1 Hz, 1H), 6.67 (s, 1H), 5 .43 (s, 2H), 4.79 (s, 1H), 2.72 (d, J = 6.6 Hz, 1H), 2.02 (s, 2H), 1.84-1.47 (m , 9H).

  Example 34: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7- (2-hydroxyethyl) -7H- Pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 7- (2-((tert-Butyldimethylsilyl) oxy) ethyl) -2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine 2,4-Dichloro-in DMF (5 mL) After stirring a solution of 7H-pyrrolo [2,3-d] pyrimidine (500 mg, 2.66 mmol) at 0 ° C. for 5 min, sodium hydride (130 mg, 3.19 mmol, 60%) was added to the solution. The resulting mixture was stirred at 0 ° C. for 15 min, and (2-bromoethoxy) (tert-butyl) dimethylsilane (904 mg, 5.32 mmol) was added. The mixture was heated to rt and stirred overnight. Water (100 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a white solid (516 mg, 56%).
MS (ESI, pos.ion) m / z: 346.95 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.35 (d, J = 3.6 Hz, 1H), 6.57 (d, J = 3.3 Hz, 1H), 4.36 (t, J = 4.9 Hz, 2H), 3.92 (t, J = 4.9 Hz, 2H), 0.83 (s, 9H), 0.08 (s, 6H).

Step 2: 3-((7- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl 7- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2,4-dichloro- in DMF (10 mL) 7H-pyrrolo [2,3-d] pyrimidine (516 mg, 1.49 mmol), 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (330 mg, 1. 64 mmol) and K ₂ CO ₃ (411 mg, 2.98 mmol) were stirred at rt overnight before the reaction was quenched with H ₂ O (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3) and the combined organic layers were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3/1) to give the title compound as a white solid (138 mg, 19%).
MS (ESI, pos.ion) m / z: 494.10 [M + H] ^< +>.

Step 3: 3-((7- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3- Yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane ( 8 mL) to 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine ( 129 mg, 0.31 mmol), K ₂ CO ₃ (120 mg, 0.84 mmol), PdCl ₂ (dppf) (22 mg, 0.03 mmol) and 3-((7- (2-((tert-butyldimethylsilyl) oxy) )ethyl ) -2-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (128 mg, 0.38 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 1.5 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (188 mg, 90% ).
MS (ESI, pos.ion) m / z: 748.15 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.75-8.69 (m, 1H), 8.67 (s, 1H), 8.32 (d, J = 1.7 Hz, 1H) 8.14 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 7.08 (d, J = 3.4 Hz, 1H), 6.36 (d, J = 3. 3 Hz, 1 H), 5.10 (d, J = 6.9 Hz, 1 H), 4.90 (s, 1 H), 4.38 (t, J = 5.4 Hz, 2 H), 3.99 (t, J = 5.4 Hz, 2H), 3.73 (s, 3H), 2.48 (d, J = 5.5 Hz, 1H), 2.39 (s, 3H), 2.08 (s, 2H) 1.98-1.70 (m, 6H), 1.64 (s, 6H), 1.53 (d, J = 14.8 Hz, 2H), 0.88 (s, 9H).

Step 4: 3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in hydrochloric acid solution (0.26 mL, 5 mol / L) in 1,4-dioxane. , 3-((7- (2-((tert-butyldimethylsilyl) oxy) ethyl) -2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (188 mg, 0.25 mmol). And the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a pale yellow solid (142 mg 89%).
MS (ESI, pos.ion) m / z: 633.20 [M + H] ^< +>.

Step 5: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7- (2-hydroxyethyl) -7H- Pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2-) in THF / MeOH (v / v = 5 mL / 5 mL) (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7- (2-hydroxyethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] A solution of octane-2-carboxylic acid (+/-)-trans-methyl (188 mg, 0.25 mmol) in sodium hydroxide (93 mg, 2.24 mmol) in water (1 mL). The solution was added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified to pH ˜6 with hydrochloric acid (1M). The mixture was extracted with ethyl acetate (15 mL × 3) and the combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (66 mg, 63%).
MS (ESI, pos.ion) m / z: 465.10 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 465.2042 [M + H] ⁺ , (C ₂₄ H ₂₆ FN ₆ O ₃ ) [M + H] ⁺ Theoretical: 465.2050;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.08 (s, 1H), 8.69 (dd, J = 9.7, 2.3 Hz, 1H), 8.26 (d, J = 1.0 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 6.7 Hz, 1H), 7.12 (d, J = 3.3 Hz) , 1H), 6.61 (d, J = 2.4 Hz, 1H), 5.00 (s, 1H), 4.79 (s, 1H), 4.26 (dd, J = 10.3, 5 .6 Hz, 2H), 3.79 (t, J = 5.7 Hz, 2H), 2.72 (d, J = 6.7 Hz, 1H), 2.02 (s, 2H), 1.87-1 .71 (m, 3H), 1.51 (m, 5H), 1.25-1.17 (m, 1H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.11, 157.13, 156.02, 155.79, 154.76, 150.37, 146.42, 131.53, 131. 25, 130.00, 124.59, 119.03, 118.96, 116.00, 115.79, 98.73, 60.74, 50.60, 49.08, 47.01, 28.95, 26.07, 24.24, 21.57, 19.51.

  Example 35: (+/-)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [ 2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide

Step 1: (3-((2-Chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) carbamic acid (+/-)-cis-tert-butyl N , N-dimethylformamide (3 mL) 2,4-dichloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine (362 mg, 1.80 mmol) and (+/-)-cis-N-tert To a solution of -butoxycarbonyl-1,3-cyclohexanediamine (350 mg, 1.63 mmol) was added potassium carbonate (677 mg, 4.90 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with H ₂ O (50 mL) and the resulting mixture was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (436 mg, 70%).
MS (ESI, pos.ion) m / z: 378.1 [M + H] ^< +>.

Step 2: (+/-) - cis ^-N 1 - (2-chloro-7-methyl -7H- pyrrolo [2,3-d] pyrimidin-4-yl) cyclohexane-1,3-diamine
To a solution of hydrochloric acid in 1,4-dioxane (0.78 mL, 3.9 mmol, 5 mol / L) was added (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine-4- Yl) amino) cyclohexyl) carbamic acid (+/-)-cis-tert-butyl (150 mg, 0.39 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo to remove the solvent and an appropriate amount of water was added to the residue. The resulting mixture was adjusted to pH 9 with saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3) and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to dryness in vacuo to give the title compound as a colorless solid As 110 mg, 100%.
MS (ESI, pos.ion) m / z: 280.1 [M + H] ^< +>.

Step 3: (+/-)-cis-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1H-1 , 2,3-Triazole-4-carboxamide (+/−)-cis-N ^1- (2-chloro-7-methyl-7H-pyrrolo [2] in a mixed solvent of tetrahydrofuran (4 mL) and dimethyl sulfoxide (1 mL) , 3-d] pyrimidin-4-yl) cyclohexane-1,3-diamine (60 mg, 0.21 mmol) in a solution of N, N-diisopropylethylamine (0.11 mL, 0.64 mmol) and 1H-1,2 , 3-triazole-4-carboxylic acid (48 mg, 0.43 mmol) was added. After the mixture was stirred at rt for 10 min, HATU (163 mg, 0.43 mmol) was added. The resulting mixture was stirred at rt for 3 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and dried to give the title compound as a colorless solid (83 mg, 100%).
MS (ESI, pos.ion) m / z: 375.2 [M + H] ^< +>.

Step 4: (+/-)-cis-N- (3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide In a microwave tube, 5-fluoro-3- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (213 mg, 0.26 mmol, 50%), (+/− ) -Cis-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole- 4-Carboxamide (80 mg, 0.21 mmol ), Potassium carbonate (88 mg, 0.64 mmol), Pd (dppf) Cl ₂ (34 mg, 0.04 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a brown solid (37 mg, 28%).
MS (ESI, pos.ion) m / z: 629.2 [M + H] ^< +>.

Step 5: (+/−)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [ 2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide (+/-)-cis-N- (3- (3- (M) (1 mL) (2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino To a solution of) cyclohexyl) -1H-1,2,3-triazole-4-carboxamide (37 mg, 0.06 mmol) was added a solution of sodium methoxide in methanol (5M, 0.12 mL, 0.6 mmol). . The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (9 mg, 32%).
MS (ESI, pos.ion) m / z: 475.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 475.2100 [M + H] ⁺ , (C ₂₃ H ₂₄ FN ₁₀ O) [M + H] ⁺ Theoretical: 475.2119;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1 H), 8.66 (d, J = 8.5 Hz, 1 H), 8.43 (s, 1 H), 8 .27 (s, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.61 (s, 1H), 4.31 (s, 1H), 4.05 (s, 1H), 3.69 (s, 3H), 2.25 (s, 1H), 2.10 (s, 1H), 1.87 (s, 2H), 1.61-1.33 (m, 4H) ).

  Example 36: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide

Step 1: (+/-)-cis-2-amino-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) Thiazole-4-carboxamide
(+/−)-cis-N ^1- (2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl in a mixed solvent of tetrahydrofuran (4 mL) and dimethyl sulfoxide (1 mL) ) To a solution of cyclohexane-1,3-diamine (62 mg, 0.22 mmol) was added N, N-diisopropylethylamine (0.11 mL, 0.66 mmol) and 2-aminothiazole-4-carboxylic acid (63 mg, 0.44 mmol). ) Was added. The mixture was stirred at rt for 10 min before HATU (168 mg, 0.44 mmol) was added. The resulting mixture was stirred at rt for 3 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and dried to give the title compound as a colorless solid (89.9 mg, 100%).
MS (ESI, pos.ion) m / z: 406.5 [M + H] ^< +>.

Step 2: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl)- 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide
To a microwave tube, add 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b]. Pyridine (221 mg, 0.27 mmol, 50%), (+/−)-cis-2-amino-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) cyclohexyl) thiazole-4-carboxamide (90 mg, 0.22 mmol), potassium carbonate (91 mg, 0.67 mmol), Pd (dppf) Cl ₂ (36 mg, 0.04 mmol), 1,4- Dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 hours with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a brown solid (56 mg, 38% ).
MS (ESI, pos.ion) m / z: 629.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, MeOD) δ (ppm): 8.80 (d, J = 8.8 Hz, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.08 ( d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.25 (s, 1H), 7.04 (d, J = 3.1 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H), 3.86 (s, 3H), 2.83 (s, 3H), 2.39 (s, 2H), 1.31 (s, 8H) .

Step 3: (+/-)-cis-2-amino-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) thiazole-4-carboxamide (+/-)-cis-2-amino-N- (3-(( 2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) To a solution of (cyclohexyl) thiazole-4-carboxamide (88 mg, 0.08 mmol) was added a solution of sodium methoxide in methanol (5M, 0.16 mL, 0.8 mmol). The mixture was stirred at rt overnight then concentrated in vacuo and the residue was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a white solid (26 mg, 62%).
MS (ESI, pos.ion) m / z: 506.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 506.1877 [M + H] ⁺ , (C ₂₄ H ₂₅ FN ₉ OS) [M + H] ⁺ Theoretical: 506.1888;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1 H), 8.66 (d, J = 8.5 Hz, 1 H), 8.43 (s, 1 H), 8 .27 (s, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.61 (s, 1H), 4.31 (s, 1H), 4.05 (s, 1H), 3.69 (s, 3H), 2.25 (s, 1H), 2.10 (s, 1H), 1.87 (s, 2H), 1.61-1.33 (m, 4H) );
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 168.62, 160.44, 156.72, 156.03, 155.54, 155.13, 146.44, 146.19, 131. 47, 131.27, 130.19, 124.68, 118.97, 116.03, 115.88, 111.66, 99.02, 47.64, 32.27, 32.15, 31.09, 29.44, 23.52, 14.42.

  Example 37: (+/-)-cis-N- (3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [ 2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide

Step 1: (+/-)-cis-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1-methyl -1H- imidazole-4-carboxamide in tetrahydrofuran (4 mL) and dimethyl sulfoxide in the mixed solvent (1mL) (+/-) - cis ^-N 1 - (2-chloro-7-methyl -7H- pyrrolo [2,3 -D] pyrimidin-4-yl) cyclohexane-1,3-diamine (110.5 mg, 9 mmol) in a solution of N, N-diisopropylethylamine (0.16 mL, 1.19 mmol) and 1-methyl-1H-imidazole. -4-carboxylic acid (99 mg, 0.78 mmol) was added. The mixture was stirred at rt for 10 min before HATU (300 mg, 0.79 mmol) was added. The resulting mixture was stirred at rt for 3 h. Water (10 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a colorless solid (86 mg, 56%).
MS (ESI, pos.ion) m / z: 388.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, MeOD) (ppm) δ: 7.65 (d, J = 6.1 Hz, 2H), 6.99 (d, J = 3.3 Hz, 1H), 6.56 (d, J = 3.4 Hz, 1 H), 3.78 (s, 3 H), 3.72 (s, 3 H), 2.68 (s, 2 H), 2.34 (d, J = 11.6 Hz, 1 H), 2.06 (s, 2H), 1.93 (d, J = 13.6 Hz, 1H), 1.61 (d, J = 13.5 Hz, 1H), 1.44 (d, J = 11.7 Hz) , 1H), 1.39 (d, J = 3.6 Hz, 2H).

Step 2: (+/-)-cis-N- (3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl- 7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide In a microwave tube, 5-fluoro-3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (249 mg, 0.30 mmol, 50%), (+/−) − Cis-N- (3-((2-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide ( 97 mg, 0.25 mmol ), Potassium carbonate (103 mg, 0.75 mmol), Pd (dppf) Cl ₂ (40 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 120 ° C. for 4 h while being heated by microwave. The reaction mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a brown solid (130 mg, 81%).
MS (ESI, pos.ion) m / z: 642.3 [M + H] ^< +>.

Step 3: (+/-)-cis-N- (3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [ 2,3-d] pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide (+/-)-cis-N- (3-((2 -(5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) cyclohexyl To a solution of) -1-methyl-1H-imidazole-4-carboxamide (130 mg, 0.20 mmol) was added a solution of sodium methoxide in methanol (5M, 0.40 mL, 2.00 mmol). The mixture was stirred at 30 ° C. overnight and then concentrated to dryness in vacuo. Water (10 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, Filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (70 mg, 71%).
MS (ESI, pos.ion) m / z: 488.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 488.2345 [M + H] ⁺ , (C25H ₂₇ FN ₉ O) [M + H] ⁺ Theoretical value: 488.2323;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.10 (s, 1H), 8.68 (d, J = 7.9 Hz, 1H), 8.34-8.20 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 11.7 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7. 05 (d, J = 3.1 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 4.31 (s, 1H), 3.98 (d, J = 8.3 Hz, 1H) ), 3.78 (s, 3H), 3.67 (s, 3H), 2.26 (d, J = 10.6 Hz, 1H), 2.12 (d, J = 10.7 Hz, 1H), 1.87 (d, J = 10.3 Hz, 2H), 1.54-1.21 (m, 4H).

  Example 38: (+/-)-trans-3-((5-fluoro-2- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine 2-methyl-1H-pyrrolo [2,3-b] pyridine (500 mg, 3.78 mmol) in DMF (8 mL) To the solution was added bromine (0.22 mL, 4.16 mmol). The reaction mixture is r.p. t. For 4 h. Saturated aqueous Na ₂ S ₂ O ₃ (100 mL) was added and the resulting mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated brine (100 mL × 3), dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow solid (679 mg, 85%).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.19 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 7.82 (d, J = 7. 8 Hz, 1H), 7.15 (dd, J = 7.8, 4.9 Hz, 1H), 2.56 (s, 3H).

Step 2: 3-bromo-2-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine 3-bromo-2-methyl-1H-pyrrolo [2,3-b] in THF (5 mL) To a solution of pyridine (100 mg, 0.47 mmol), NaH (22 mg, 0.57 mmol, 60%) was added at 0 ° C. The reaction mixture was then stirred at 0 ° C. for 30 min. TsCl (100 mg, 0.52 mmol) was added and the reaction mixture was stirred at rt overnight. Water (50 mL) was added to quench the reaction and the resulting mixture was partitioned. The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow solid (100 mg, 58%).
MS (ESI, pos.ion) m / z: 365.95 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.44 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.24 (dd, J = 7.8, 4.9 Hz, 1H), 2.79 ( s, 3H), 2.39 (s, 3H).

Step 3: 2-Methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine DME 3-bromo-2-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine (100 mg, 0.27 mmol), Pd (dppf) Cl ₂ (20 mg, 0.03 mmol) and (5 mL) After replacing the air in the suspension of KOAc (80 mg, 0.82 mmol) with nitrogen, bis (pinacolato) diboron (104 mg, 0.41 mmol) was added to the mixture. After the mixture was purged with nitrogen for 10 min by bubbling to remove air, the mixture was stirred at 105 ° C. for 2 h with microwave heating. To the reaction mixture was added ethyl acetate (20 mL) and the mixture was filtered through a celite pad. The filter cake was washed with ethyl acetate (20 mL × 2). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to give the title compound as a yellow solid (60 mg, 53%). .
MS (ESI, pos.ion) m / z: 413.45 [M + H] ^< +>.

Step 4: 3-((5-Fluoro-2- (2-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (10 mL) to 2-methyl-3- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (50 mg, 0.12 mmol), K ₂ CO ₃ (50 mg, 0.36 mmol), PdCl ₂ (dppf) (10 mg, 0.01 mmol) and 3-((2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (41 mg, 0.13 mmol). Addition did. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. for 1.5 h while heating with microwave for 10 min. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (18 mg, 26% ).

Step 5: (+/−)-trans-3-((5-fluoro-2- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-Fluoro-2- (2-methyl-1-tosyl-1H-pyrrolo) in THF / MeOH (v / v = 5 mL / 5 mL) [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (130 mg, 0.23 mmol) ) Was added a solution of NaOH (95 mg, 2.31 mmol) in water (1 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to pH ˜6. The resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (32 mg, 35%).
MS (ESI, pos.ion) m / z: 396.15 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 396.1836 [M + H] ⁺ , (C ₂₁ H ₂₃ FN ₅ O ₂ ) [M + H] ⁺ Theoretical: 396.1836;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.49 (s, 1H), 8.61 (d, J = 7.7 Hz, 1H), 8.43 (d, J = 4. 9 Hz, 1H), 8.34 (d, J = 4.5 Hz, 1H), 8.28 (s, 1H), 7.24 (dd, J = 7.5, 4.8 Hz, 1H). 76 (t, J = 6.6 Hz, 1H), 2.90 (d, J = 6.8 Hz, 1H), 2.81 (s, 3H), 2.02 (s, 1H), 1.89 ( s, 1H), 1.76 (d, J = 8.2 Hz, 2H), 1.66 (d, J = 10.6 Hz, 1H), 1.59 (d, J = 6.2 Hz, 1H), 1.54-1.31 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 175.75, 156.88, 152.63, 146.57, 143.67, 142.67, 142.10, 141.59, 130. 17, 120.33, 117.15, 107.09, 51.22, 47.55, 29.18, 28.65, 25.58, 24.18, 21.48, 19.49, 14.49.

  Example 39: (+/-)-trans-3-((2- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (2-Methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (10 mL) to 2-methyl-3- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (100 mg, 0.24 mmol), K ₂ CO ₃ (100 mg, 0.73 mmol), Pd (dppf) Cl ₂ (18 mg, 0.03 mmol) and 3-((2-chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans- Methyl (99mg 0.27 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 3 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (130 mg, 86% ).
MS (ESI, pos.ion) m / z: 623.15 [M + H] ^< +>.

Step 2: (+/-)-trans-3-((2- (2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (2-methyl-1-tosyl-1H-pyrrolo [2,3]) in THF / MeOH (v / v = 5 mL / 5 mL) -B] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (130 mg, 0.21 mmol) ) Was added a solution of sodium hydroxide (85 mg, 2.09 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified to pH ˜6 with hydrochloric acid (1M). The mixture was extracted with ethyl acetate (15 mL × 3) and the combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (38 mg, 40%).
MS (ESI, pos.ion) m / z: 454.20 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 454.2261 [M + H] ⁺ , (C ₂₇ H ₂₈ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 454.2243;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 11.91 (s, 1H), 8.90 (d, J = 7.1 Hz, 1H), 8.21-8.15 (m, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.58-7.48 (m, 3H), 7.40 (d, J = 5.5 Hz, 1H), 7.14 ( dd, J = 7.8, 4.7 Hz, 1H), 6.71 (s, 1H), 3.94 (s, 1H), 2.96 (s, 3H), 1.85-1.51 ( m, 8H), 1.23 (d, J = 3.1 Hz, 4H).

  Example 40: (+/−)-trans-3-((7-methyl-2- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((7-Methyl-2- (2-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-b] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 2-methyl-3- (4,4,4). 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (100 mg, 0.24 mmol), K ₂ CO ₃ (100 mg, 0.73 mmol), Pd (dppf) Cl ₂ (24 mg, 0.02 mmol) and 3-((2-chloro-7-methyl-7H-pyrrolo [2,3-b] pyrimidin-4-yl) amino) bicyclo [2.2.2] Octane-2- Carboxylic acid (+/−)-trans-methyl (99 mg, 0.27 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 1.5 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (112 mg, 77% ).
MS (ESI, pos.ion) m / z: 599.20 [M + H] ^< +>.

Step 2: (+/-)-trans-3-((7-methyl-2- (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((7-methyl-2- (7) in THF / MeOH (v / v = 5 mL / 5 mL)) 2-Methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7H-pyrrolo [2,3-b] pyrimidin-4-yl) amino) bicyclo [2.2.2 To a solution of octane-2-carboxylic acid (+/−)-trans-methyl (113 mg, 0.19 mmol) was added a solution of sodium hydroxide (79 mg, 1.89 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified to pH ˜6 with hydrochloric acid. The mixture was extracted with ethyl acetate (15 mL × 3) and the combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (31 mg, 38% ).
MS (ESI, pos.ion) m / z: 431.15 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 431.2201 [M + H] ⁺ , (C ₂₄ H ₂₇ N ₆ O ₂ ) [M + H] ⁺ Theoretical value: 431.2195;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm) 11.73 (s, 1H), 8.95 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 4.4 Hz) , 1H), 7.16 (d, J = 7.1 Hz, 1H), 7.10 (dd, J = 7.8, 4.7 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.60 (s, 1H), 4.83 (s, 1H), 3.77 (s, 3H), 2.94 (s, 3H), 2.74 (d, J = 6.7 Hz) , 1H), 2.00 (d, J = 15.2 Hz, 2H), 1.76 (d, J = 10.5 Hz, 2H), 1.62-1.34 (m, 5H), 1.24 (S, 2H).

  Example 41: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Bromo-5-fluoropyridin-2-amine To a solution of 5-fluoropyridin-2-amine (6 g, 53.52 mmol) in acetonitrile (120 mL), NBS (12.64 g, 69.60 mmol). Was slowly added and the mixture was stirred at rt for 2 h before being concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 20/1) to give the title compound as a yellow solid (5.4 g, 53%).
MS (ESI, pos.ion) m / z: 193.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.95 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 7.3, 2.6 Hz, 1H); 84 (s, 2H).

Step 2: 5-Fluoro-3-((4-fluorophenyl) ethynyl) pyridin-2-amine 3-Bromo-5-fluoropyridin-2-amine (1.33 g, 6.96 mmol) in acetonitrile (14 mL). To this solution was added in turn triethylamine (14 mL), 1-ethynyl-4-fluorobenzene (850 mg, 7.08 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (496 mg, 0.70 mmol) and the mixture was nitrogen protected. Then, the mixture was stirred at 75 ° C. for 6 hours and then concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 10/1) to give the title compound as a yellow solid (770 mg, 48.0%).
MS (ESI, pos.ion) m / z: 231.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.95 (d, J = 2.9 Hz, 1H), 7.56-7.48 (m, 2H), 7.38 (dd, J = 8.3, 2.9 Hz, 1H), 7.09 (dd, J = 11.0, 4.3 Hz, 2H), 4.96 (s, 2H).

Step 3: 5-Fluoro-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridine 5-fluoro-3-((4-fluorophenyl) ethynyl) pyridine in DMF (1 mL) To a solution of 2-amine (50 mg, 0.22 mmol) was added potassium tert-butoxide (73 mg, 0.65 mmol) and the mixture was stirred at 80 ° C. for 3 h under nitrogen protection and then cooled to room temperature. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 2/1) to give the title compound as a white solid (30 mg, 60%).
MS (ESI, pos.ion) m / z: 231.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 12.29 (s, 1H), 8.19 (s, 1H), 8.00 (dd, J = 8.6, 5.4 Hz, 2H) 7.83 (dd, J = 9.5, 2.6 Hz, 1H), 7.34 (t, J = 8.8 Hz, 2H), 6.92 (s, 1H).

Step 4: 3-Bromo-5-fluoro-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridine 5-fluoro-2- (4-fluorophenyl)-in DMF (1 mL) To a solution of 1H-pyrrolo [2,3-b] pyridine (30 mg, 0.13 mmol) was added bromine (0.02 mL, 0.26 mmol). The reaction mixture was stirred at rt for 2 h. Saturated aqueous Na ₂ S ₂ O ₃ (20 mL) was added and the resulting mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with saturated brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 2/1) to give the title compound as a white solid (15 mg, 37%).
MS (ESI, pos.ion) m / z: 311.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.65 (s, 1H), 8.32 (s, 1H), 7.94 (dd, J = 8.6, 5.5 Hz, 2H), 7.76 (dd, J = 8.8, 2.5 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H).

Step 5: 3-Bromo-5-fluoro-2- (4-fluorophenyl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine To dry tetrahydrofuran (10 mL), 3-bromo-5-fluoro 2- (4-Fluorophenyl) -1H-pyrrolo [2,3-b] pyridine (0.74 g, 2.0 mmol) was added. To the solution was added sodium hydride (232 mg, 5.80 mmol, 60%) at 0 ° C. and the resulting mixture was stirred at 0 ° C. for 30 min. P-Toluenesulfonyl chloride (667 mg, 3.50 mmol) was then added to the mixture and the mixture was heated to rt and stirred for 3 h. Water (100 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (360 mg, 27%).
MS (ESI, pos.ion) m / z: 463.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.42 (d, J = 1.2 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.53-7. 47 (m, 3H), 7.28-7.19 (m, 4H).

Step 6: 5-Fluoro-2- (4-fluorophenyl) -1-tosyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2, 3-b] pyridine 3-Bromo-5-fluoro-2- (4-fluorophenyl) -1- (p-tolylsulfonyl) pyrrolo [2,3-b] pyridine (300 mg, 0.65 mmol) in a microwave tube Bis (pinacolato) diboron (247 mg, 0.97 mmol), potassium acetate (128 mg, 1.30 mmol), Pd (dppf) Cl ₂ (53 mg, 0.06 mmol) and dimethoxyethane (4 mL). Air in the mixture was removed by bubbling with nitrogen for 10 min, and the mixture was stirred at 130 ° C. for 2 h while being heated with microwaves. The mixture was cooled to room temperature and filtered through a celite pad. The filter cake was ethyl acetate (10 mL) and the combined filtrates were dried in vacuo and dried. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a yellow oil (220 mg, 67%).
MS (ESI, pos.ion) m / z: 511.4 [M + H] ^< +>.

Step 7: 3-((5-Fluoro-2- (5-fluoro-2- (4-fluorophenyl) -1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-2- (4-fluorophenyl) -1-tosyl in a sealed tab-type container -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b] pyridine (200 mg, 0.38 mmol), 3-((2- Chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.32 mmol), potassium carbonate (132 mg, 0 .96mmo l), Pd (dppf) Cl ₂ (52 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. The mixture was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (204 mg, 97%) .
MS (ESI, pos.ion) m / z: 662.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.40 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 8.8, 2.8 Hz, 1H), 7. 96 (d, J = 3.1 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.43 (s, 2H), 7.13 (t, J = 8. 5Hz, 2H), 3.81 (s, 1H), 3.60 (s, 3H), 2.37 (s, 3H), 2.25 (d, J = 7.1 Hz, 1H), 1.58 (M, 8H).

Step 8: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-3-yl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5) in THF / MeOH (v / v = 1/1, 3 mL). 5-Fluoro-2- (4-fluorophenyl) -1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.30 mmol) was added aqueous sodium hydroxide (4M, 0.75 mL, 3.00 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 5.5, and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (74 mg, 50%).
HRMS (ESI, pos.ion) m / z: 494.1824 [M + H] ⁺ , (C ₂₆ H ₂₃ F ₃ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 494.1804;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.35 (s, 1H), 8.41 (dd, J = 9.9, 2.6 Hz, 1H), 8.26 (s, 1H), 8.11 (d, J = 3.6 Hz, 1H), 7.95 (s, 1H), 7.67 (dd, J = 8.3, 5.6 Hz, 2H), 7.48 ( d, J = 7.0 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 4.24 (t, J = 7.1 Hz, 1H), 2.76 (d, J = 7) .3 Hz, 1 H), 1.94 (s, 1 H), 1.66 (d, J = 8.5 Hz, 2 H), 1.50 (s, 1 H), 1.37-1.20 (m, 6 H) ).

  Example 42: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 5-Fluoro-3- (2-phenylethynyl) pyridin-2-amine To a solution of 3-bromo-5-fluoropyridin-2-amine (3.8 g, 20 mmol) in acetonitrile (40 mL) was added triethylamine. (40 mL), phenylacetylene (2.2 g, 22 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (1.5 g, 2.1 mmol) were added in turn and the mixture was stirred at 75 ° C. for 5 h under nitrogen protection. Concentrated in vacuo and dried. The residue was purified by silica gel column chromatography (PE / EA (v / v) = 10/1) to give the title compound as a yellow solid (2.9 g, 69%).
MS (ESI, pos.ion) m / z: 213.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.95 (d, J = 2.9 Hz, 1H), 7.56-7.48 (m, 2H), 7.38 (dd, J = 8.3, 2.9 Hz, 1H), 7.09 (dd, J = 11.0, 4.3 Hz, 2H), 4.96 (s, 2H).

Step 2: 5-Fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridine 5-Fluoro-3- (2-phenylethynyl) pyridin-2-amine (2.8 g, in DMF (30 mL)) 13 mmol) was added potassium tert-butoxide (4.4 g, 39 mmol) and the mixture was stirred at 80 ° C. for 3 h under nitrogen protection and then cooled to rt. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 2/1) to give the title compound as a white solid (2.5 g, 89%).
MS (ESI, pos.ion) m / z: 213.1 [M + H] ^< +>.

Step 3: 3-Bromo-5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridine 5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] in DMF (30 mL) To a solution of pyridine (2.5 g, 30 mmol) bromine (1.2 mL, 23 mmol) was added. The reaction mixture was stirred at rt for 2 h. Saturated aqueous Na ₂ S ₂ O ₃ (50 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 2/1) to give the title compound as a white solid (3.20 g, 93%).
MS (ESI, pos.ion) m / z: 291.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.92 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7 .65 (dd, J = 8.4, 2.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 7.4 Hz, 1H).

Step 4: 3-Bromo-5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine 3-Bromo-5-fluoro-2-phenyl-in dry tetrahydrofuran (40 mL) To a solution of 1H-pyrrolo [2,3-b] pyridine (3.84 g, 13.2 mmol) was added sodium hydride (1.07 g, 26.8 mmol, 60%). After the reaction mixture was stirred at 0 ° C. for 30 min, p-toluenesulfonyl chloride (3.03 g, 15.9 mmol) was added. The resulting mixture was stirred at rt for 3 h before being quenched with water (100 mL) and the mixture was partitioned. The aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (1.42 g, 24%).
MS (ESI, pos.ion) m / z: 444.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.41 (d, J = 1.3 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.56 −7.49 (m, 6H), 7.23 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H).

Step 5: 5-Fluoro-2-phenyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3- b] pyridine 3-Bromo-5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine (1.35 g, 3.03 mmol), bis (pinacolato) diboron ( 1.15 g, 4.53 mmol), potassium acetate (596 mg, 6.07 mmol), Pd (dppf) Cl ₂ (249 mg, 0.30 mmol) and dimethoxyethane (10 mL) were charged. The mixture was stirred at 130 ° C. for 2 h with microwave heating. The mixture was cooled to rt and filtered through a celite pad. The filter cake was washed with ethyl acetate (10 mL) and the combined filtrates were vacuum dried and dried. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a white solid (1.14 g, 76%).
MS (ESI, pos.ion) m / z: 493.1 [M + H] ^< +>.

Step 6: 3-((5-Fluoro-2- (5-fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl In a sealed tube, 5-fluoro-2-phenyl-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (158 mg, 0.31 mmol), 3-((2-chloro-5-fluoropyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (80 mg, 0.25 mmol), potassium carbonate (106 mg, 0.77 mmol), Pd (dppf) Cl ₂ (42 mg, 0.05 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 2 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (29 mg, 18%) .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.40 (d, J = 1.8 Hz, 1H), 8.19 (dd, J = 8.7, 2.8 Hz, 1H), 7. 95 (d, J = 3.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 6.0 Hz, 5H), 7.21 (d, J = 8.0 Hz, 2H), 4.85 (d, J = 7.4 Hz, 1H), 4.08 (t, J = 6.8 Hz, 1H), 3.59 (s, 3H), 2.37. (S, 3H), 2.22 (d, J = 6.6 Hz, 1H), 2.04 (s, 2H), 1.57-1.28 (m, 8H).

Step 7: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-fluoro-2) in THF / MeOH (v / v = 1/1, 3 mL) -Phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -To a solution of trans-methyl (29 mg, 0.05 mmol) was added aqueous sodium hydroxide (4M, 0.13 mL, 0.50 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (19 mg, 89%).
MS (ESI, pos.ion) m / z: 476.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 476.1900 [M + H] ⁺ , (C ₂₆ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 476.1898;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.31 (s, 1H), 8.38 (dd, J = 9.9, 2.7 Hz, 1H), 8.26 (s, 1H), 8.08 (d, J = 3.7 Hz, 1H), 7.61 (d, J = 6.9 Hz, 2H), 7.51-7.37 (m, 4H), 4.28 ( s, 1H), 2.76 (d, J = 6.8 Hz, 1H), 1.93 (s, 1H), 1.66 (d, J = 8.5 Hz, 2H), 1.57-1. 28 (m, 8H).

  Example 43: (+/-)-trans-3-((2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (5-Fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl In a sealed tube, 5-fluoro-2-phenyl-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (133 mg, 0.26 mmol), 3-((2-chloro-6-phenylpyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (80 mg, 0.22 mmol), potassium carbonate (90 mg, 0.65 mmol), Pd (dppf) Cl (36mg, 0.04mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture in the sealed tube was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (57 mg, 38%) .
MS (ESI, pos.ion) m / z: 702.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.48 (d, J = 9.0 Hz, 1H), 8.43 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.55-7.47 (m, 6H), 7.39 (d, J = 6.8 Hz, 1H), 7.36-7.31 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.63 (s, 1H), 4.92 (s, 1H), 4.35 (s, 1H), 3.67 (s, 3H), 2.41-2 .31 (m, 4H), 1.88 (s, 1H), 1.83-1.59 (m, 8H).

Step 2: (+/-)-trans-3-((2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-2-phenyl) in THF / MeOH (v / v = 1/1, 1.0 mL) -1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / To a solution of −)-trans-methyl (51 mg, 0.07 mmol) was added aqueous sodium hydroxide (4M, 0.15 mL, 0.70 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (35 mg, 90%).
MS (ESI, pos.ion) m / z: 534.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 534.2317 [M + H] ⁺ , (C ₃₂ H ₂₉ FN ₅ O ₂ ) [M + H] ⁺ Theoretical: 534.2305;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.38 (s, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.72-7.63 (M, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.50-7.31 (m, 7H), 6.71 (s, 1H), 4.50 (s, 1H) ), 2.89 (s, 1H), 2.73 (s, 1H), 1.99 (s, 1H), 1.79 (s, 1H), 1.76-1.40 (m, 8H) .

  Example 44: (+/-)-trans-3-((2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (5-Fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl In a sealed tube, 5-fluoro-2-phenyl-3- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (174 mg, 0.34 mmol), 3- ( (2-Chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicycle [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (100 mg, 0.29 mmol), potassium carbonate (118 mg, 0.86 mmol), Pd (dppf) Cl ₂ (47 mg, 0.06 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (58 mg, 30%) .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.52 (dd, J = 9.0, 2.8 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7. 87 (s, 1H), 7.85 (s, 1H), 7.52 (d, J = 6.6 Hz, 2H), 7.47-7.39 (m, 3H), 7.23 (s, 1H), 7.21 (s, 1H), 6.84 (d, J = 3.4 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H), 4.80 (d, J = 7.6 Hz, 1H), 4.62 (t, J = 7.1 Hz, 1H), 3.59 (s, 3H), 3.41 (s, 3H), 2.38 (s, 3H), 2 .33 (d, J = 6.6 Hz, 1H), 1.92 (s, 2H), 1.71-1.63 (m, 6H), 1.49 (d, J = 10.6 Hz, 2H) .

Step 2: (+/-)-trans-3-((2- (5-fluoro-2-phenyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3- (in THF / MeOH (v / v = 1/1, 1.0 mL) (2- (5-Fluoro-2-phenyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidine-4 -Il) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (58 mg, 0.09 mmol) in water (4 M, 0.23 mL, 0.90 mmol). A solution of sodium hydroxide in) was added. The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (29 mg, 66%).
MS (ESI, pos.ion) m / z: 511.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 51.2267 [M + H] ⁺ , (C ₂₉ H ₂₈ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 511.2258;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.21 (s, 1H), 8.61 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7 .71 (d, J = 6.8 Hz, 2H), 7.48-7.37 (m, 3H), 7.18 (d, J = 6.9 Hz, 1H), 7.04 (d, J = 3.3 Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 4.53 (t, J = 6.9 Hz, 1H), 3.49 (s, 3H), 2.66 ( d, J = 7.1 Hz, 1H), 1.97 (s, 1H), 1.79-1.66 (m, 4H), 1.49-1.29 (m, 6H).

  Example 45: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 5-Fluoro-3-iodo-4-methylpyridin-2-amine To a solution of 5-fluoro-4-methylpyridin-2-amine (2.00 g, 15.9 mmol) in glacial acetic acid (13 mL). , Trifluoroacetic acid (0.13 mL) and NIS (3.75 g, 16.2 mmol) were added. The mixture was stirred at rt overnight and then poured into ice water (50 mL). The resulting mixture was adjusted to pH 9 with concentrated ammonia and then filtered. The filter cake was washed with water and dried in vacuo to give a yellow solid (2.87 g, 72%).
MS (ESI, pos.ion) m / z: 252.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.83 (s, 1H), 4.89 (s, 3H), 2.37 (d, J = 2.0 Hz, 2H).

Step 2: 5-Fluoro-4-methyl-3-((trimethylsilyl) ethynyl) pyridin-2-amine 5-fluoro-3-iodo-4-in in a mixed solvent of triethylamine (58 mL) and tetrahydrofuran (11.6 mL) To a solution of methylpyridin-2-amine (2.88 g, 11.4 mmol) was added Pd (PPh ₃ ) ₂ Cl ₂ (810 mg, 1.14 mmol), cuprous iodide (435 mg, 2.28 mmol) and trimethylsilylacetylene. (3.23 mL, 22.9 mmol) was added. The mixture was stirred at rt overnight under nitrogen protection and diluted with saturated aqueous ammonium chloride (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a dark solid ( 1.72 g, 68%).
MS (ESI, pos.ion) m / z: 223.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.83 (s, 1H), 2.33 (d, J = 1.4 Hz, 3H), 0.30 (s, 9H).

Step 3: 5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridine 5-fluoro-4-methyl-3-((trimethylsilyl) ethynyl) pyridin-2-amine in DMF (16 mL) ( To a solution of 1.72 g, 7.74 mmol) was added potassium tert-butoxide (2.60 g, 23.2 mmol) and the mixture was stirred at 80 ° C. for 1 h under nitrogen protection and then cooled to rt. Water (100 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5/1) to give the title compound as a white solid (550 mg, 47%).
MS (ESI, pos.ion) m / z: 151.1 [M + H] ⁺ ;
¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 9.62 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.42-7.33 (m, 1H) 6.53 (dd, J = 3.1, 2.1 Hz, 1H), 2.53 (d, J = 1.0 Hz, 3H).

Step 4: 3-Bromo-5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridine 5-fluoro-4-methyl-1H-pyrrolo [2,3-b] in DMF (8 mL) To a solution of pyridine (540 mg, 3.60 mmol) bromine (0.37 mL, 7.19 mmol) was added. The reaction mixture was stirred at rt for 2 h. Saturated aqueous Na ₂ S ₂ O ₃ (50 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a white solid (760 mg, 92%).
MS (ESI, pos.ion) m / z: 231.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 2. 6 Hz, 1H), 2.66 (s, 3H).

Step 5: 3-Bromo-5-fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine To dry tetrahydrofuran (10 mL), add 3-bromo-5-fluoro-4-methyl- 1H-pyrrolo [2,3-b] pyridine (760 mg, 3.32 mmol) was added. To the solution was added sodium hydride (265 mg, 6.63 mmol, 60%) at 0 ° C. and the resulting mixture was stirred at 0 ° C. for 30 min. P-Toluenesulfonyl chloride (759 mg, 3.98 mmol) was then added to the mixture and the mixture was heated to rt and stirred overnight. Water (100 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (840 mg, 66%).
MS (ESI, pos.ion) m / z: 382.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.24 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.31 (D, J = 8.2 Hz, 2H), 2.68 (d, J = 1.3 Hz, 3H), 2.40 (s, 3H).

Step 6: 5-Fluoro-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3- b] Pyridine To a microwave tube, add 3-bromo-5-fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine (400 mg, 1.04 mmol), bis (pinacolato) diboron (397 mg). 1.56 mmol), potassium acetate (204 mg, 2.08 mmol), Pd (dppf) Cl ₂ (85 mg, 0.10 mmol) and dimethoxyethane (5 mL). Air in the mixture was removed by bubbling with nitrogen for 10 min, and the mixture was stirred at 130 ° C. for 2 h with microwave heating. The mixture was cooled to rt and filtered through a celite pad. The filter cake was washed with ethyl acetate (10 mL) and the combined filtrates were concentrated in vacuo and dried. The residue was purified by silica gel chromatography (n-hexane / EtOAc (v / v) = 10/1) to give the title compound as a white solid (352 mg, 78%).
MS (ESI, pos.ion) m / z: 431.0 [M + H] ^< +>.

Step 7: 3-((5-Fluoro-2- (5-fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl) in a sealed tab-type container -1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (163 mg, 0.38 mmol), 3-((2-chloro-5-fluoropyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol), Pd (dppf ) Cl (52mg, 0.06mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (120 mg, 65%) .
MS (ESI, pos.ion) m / z: 582.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.25 (d, J = 9.4 Hz, 2H), 8.10 (dd, J = 11.7, 5.7 Hz, 3H), 7. 30 (s, 1H), 5.19 (d, J = 5.5 Hz, 1H), 4.68 (s, 1H), 3.52 (s, 3H), 2.62 (d, J = 1. 9 Hz, 3H), 2.45 (d, J = 5.5 Hz, 1H), 2.39 (s, 3H), 2.04 (s, 1H), 1.95 (s, 2H), 1.87. -1.62 (m, 8H).

Step 8: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-fluoro-4) in THF / MeOH (v / v = 1/1, 4 mL) -Methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) To a solution of trans-methyl (120 mg, 0.21 mmol) was added aqueous sodium hydroxide solution (4M, 0.53 mL, 2.10 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (32 mg, 38%).
MS (ESI, pos.ion) m / z: 414.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 414.1750 [M + H] ⁺ , (C ₂₁ H ₂₂ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 414.1742;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.31 (s, 1H), 12.07 (s, 1H), 8.55 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.10 (s, 2H), 7.60-7.38 (m, 4H), 6.76 (s, 1H), 4.64 (s, 1H), 2. 53 (d, J = 2.5 Hz, 4H), 1.99 (s, 2H), 1.86-1.39 (m, 8H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 175.93, 167.43, 158.37, 158.31, 156.07, 153.72, 151.71, 151.60, 146. 15, 138.48, 138.31, 132.21, 132.02, 131.80, 131.45, 131.14, 129.11, 126.98, 126.81, 117.69, 67.90, 50.33, 48.21, 38.59, 30.28, 29.08, 28.83, 28.74, 25.74, 24.27, 23.74, 22.84, 21.48, 19. 43, 14.32, 13.61, 13.56, 11.25.

  Example 46: (+/-)-trans-3-((2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (5-Fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl In a sealed tube, 5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (112 mg, 0.26 mmol), 3-((2-chloro-6-phenylpyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (80 mg, 0.22 mmol), potassium carbonate (89 mg, 0.65 mmol), Pd (dppf) Cl ₂ ( 5 mg, 0.04 mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (92 mg, 67%) .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.37 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 8.07 (D, J = 5.6 Hz, 2H), 7.54-7.46 (m, 3H), 7.30 (s, 1H), 6.83 (s, 1H), 5.29 (s, 1H) ), 4.46 (s, 1H), 3.69 (s, 3H), 2.67 (s, 3H), 2.46 (d, J = 5.1 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 1H), 1.96-1.94 (m, 1H), 1.71 (m, 8H).

Step 2: (+/-)-trans-3-((2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-4-methyl-1) in THF / MeOH (v / v = 1/1, 4 mL) -Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) To a solution of trans-methyl (92 mg, 0.14 mmol) was added aqueous sodium hydroxide (4M, 0.33 mL, 1.40 mmol). The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (49 mg, 72%).
MS (ESI, pos.ion) m / z: 472.5 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 472.2147 [M + H] ⁺ , (C ₂₇ H ₂₇ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 472.2149;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.13 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 8.04 (s, 2H) ), 7.51 (d, J = 7.6 Hz, 4H), 6.81 (s, 1H), 4.61 (s, 1H), 2.84 (s, 3H), 1.96 (s, 1H), 1.83-1.39 (m, 10H).

  Example 47: (+/-)-trans-3-((2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (5-Fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl In a sealed tube, 5-fluoro-4-methyl-3- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (91 mg, 0.21 mmol), 3- ( (2-Chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (60 mg, 0.17 mmol), potassium carbonate (71 m g, 0.51 mmol), Pd (dppf) Cl ₂ (28 mg, 0.03 mmol), 1,4-dioxane (3 mL) and water (0.2 mL) were added. The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 ° C. for 4 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (77 mg, 73%) .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.32 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 6.96 (D, J = 3.4 Hz, 1H), 6.45 (s, 1H), 5.18 (s, 1H), 4.78 (s, 1H), 3.82 (s, 3H), 3. 77 (s, 1H), 3.54 (s, 3H), 2.68 (s, 3H), 2.47 (d, J = 5.1 Hz, 1H), 2.39 (s, 3H), 2 .03 (s, 2H), 1.90-1.62 (m, 8H).

Step 2: (+/-)-trans-3-((2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2) in THF / MeOH (v / v = 1/1, 4 mL) -(5-Fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (75 mg, 0.12 mmol) was added to a solution of sodium hydroxide in water (4M, 0.30 mL, 1 .20 mmol) was added. The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (19 mg, 35%).
MS (ESI, pos.ion) m / z: 449.5 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 449.2115 [M + H] ⁺ , (C ₂₄ H ₂₆ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 449.2101;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.09 (s, 1H), 8.26-8.07 (m, 2H), 7.96 (d, J = 2.1 Hz, 1H), 7.78-7.59 (m, 1H), 7.50 (d, J = 6.8 Hz, 1H), 4.64 (s, 1H), 4.14 (s, 1H), 2 .79 (s, 4H), 1.97 (s, 1H), 1.63 (m, 8H).

  Example 48: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2,6-Dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a reaction flask 2,4,6-trichloro-5-fluoropyrimidine (10.00 g, 49.65 mmol), potassium carbonate (21.00 g, 148.90 mmol), 3-aminobicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (10.00 g, 54.61 mmol) and DMF (50 mL) were added. The mixture was stirred at rt for 5 h. When the reaction was complete, water (100 mL) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a pale yellow solid (12.00 g, 69% ).
MS (ESI, pos.ion) m / z: 348.10 [M + H] ^< +>.

Step 2: 3-((2-Chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl acetonitrile (100 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl ( 2.00 g, 5.74 mmol), phenylboronic acid (0.70 g, 5.74 mmol), potassium acetate (1.70 g, 17.2 mmol) and Pd (dppf) Cl ₂ (0.50 g, 0.57 mmol). After the addition, water (5 mL) was added to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (430 mg, 19%).
MS (ESI, pos.ion) m / z: 390.1 [M + H] ^< +>.

Step 3: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5-tetramethyl-1,3. , 2-Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (670 mg, 0.97 mmol, 60%), potassium carbonate (570 mg, 4.10 mmol), palladium acetate (23 mg , 0.10 mmol), XPhos (100 mg, 0.20 mmol) and 3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid (+/−)-trans-methyl (400 mg, 1.02 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the mixture was heated to 110 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (200 mg, 30%).
MS (ESI, pos.ion) m / z: 644.3 [M + H] ^< +>.

Step 4: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-fluoro-1-tosyl) in a mixed solvent of THF (8 mL) and MeOH (4 mL) -1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans To a solution of methyl (200 mg, 0.31 mmol) was added a solution of NaOH (124 mg, 3.10 mmol) in water (2 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (100 mg, 68%).
MS (ESI, pos.ion) m / z: 476.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 476.1816 [M + H] ⁺ , (C ₂₆ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 476.1898;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.52 (s, 1 H), 12.26 (s, 1 H), 8.68 (d, J = 8.0 Hz, 1 H), 8 .37 (d, J = 7.6 Hz, 3H), 8.25 (s, 1H), 7.53 (m, 4H), 4.70 (s, 1H), 3.58 (s, 2H), 2.89 (d, J = 6.2 Hz, 1H), 2.17 (s, 1H), 2.01 (s, 1H), 1.95 (s, 1H), 1.50 (m, 5H) .

  Example 49: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl acetonitrile (100 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl (2.00 g, 5.74 mmol), 2-furanboronic acid (0.65 g, 5.74 mmol), potassium acetate (1.70 g, 17.2 mmol) and Pd (dppf) Cl ₂ (. 50 g, 0.57 mmol) was added followed by water (5 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (700 mg, 30%).
MS (ESI, pos.ion) m / z: 380.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (390 mg, 0.55 mmol, 60%), potassium carbonate (290 mg, 2.10 mmol) ), Palladium acetate (11 mg, 0.05 mmol), XPhos (50 mg, 0.10 mmol) and 3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) bicyclo [2 2.2.2] Octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 1.02 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the mixture was heated to 100 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (250 mg, 75%).
MS (ESI, pos.ion) m / z: 634.2 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5) in THF / MeOH (v / v = 8 mL / 4 mL) -Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (+/-)-trans-methyl (250 mg, 0.40 mmol) was added a solution of sodium hydroxide (140 mg, 4.00 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (120 mg, 54% ).
MS (ESI, pos.ion) m / z: 466.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 466.1699 [M + H] ⁺ , (C ₂₄ H ₂₂ F ₂ N ₅ O ₃ S) [M + H] ⁺ Theoretical: 466.1691;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8. 8 Hz, 2H), 8.00 (s, 1H), 7.61 (d, J = 5.8 Hz, 1H), 7.24 (s, 1H), 6.75 (s, 1H), 4.71 (S, 1H), 2.88 (d, J = 5.5 Hz, 1H), 2.01 (s, 1H), 1.98 (s, 1H), 1.77 (m, 3H), 1. 50 (m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.04, 157.58, 157.32, 154.993, 152.60, 148.55, 146.40, 145.65, 140. 32, 137.72, 137.24, 131.91, 131.62, 131.24, 118.82, 115.48, 114.30, 112.64, 51.14, 48.29, 40.40, 40.20, 39.99, 39.78.

  Example 50: (+/−)-trans-3-((6-([1,1′-biphenyl] -4-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3 -B] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((6-([1,1′-biphenyl] -4-yl) -2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2 Carboxylic acid (+/-)-trans-methyl acetonitrile (50 mL) to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2 -Carboxylic acid (+/-)-trans-methyl (1.00 g, 2.87 mmol), [1,1'-biphenyl] -4-ylboronic acid (0.57 g, 2.87 mmol), potassium acetate (0. After adding 85 g, 8.62 mmol) and Pd (dppf) Cl ₂ (0.25 g, 0.28 mmol), water (2 mL) was added to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (600 mg, 45%).
MS (ESI, pos.ion) m / z: 466.0 [M + H] ^< +>.

Step 2: 3-((6-([1,1′-biphenyl] -4-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine) -3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL), 5-fluoro-3- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (450 mg, 0.64 mmol, 60%), carbonic acid Potassium (355 mg, 2.57 mmol), palladium acetate (14 mg, 0.06 mmol), XPhos (61 mg, 0.12 mmol) and 3-((6-([1,1′-biphenyl] -4-yl) -2 -Chloro-5-full Ropirimijin 4-yl) amino) Bishikuru [2.2.2] octane-2-carboxylic acid (+/-) - trans - was added methyl (300 mg, 0.64 mmol). H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (300 mg, 65%).
MS (ESI, pos.ion) m / z: 720.1 [M + H] ^< +>.

Step 3: (+/−)-trans-3-((6-([1,1′-biphenyl] -4-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3 -B] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6) in a mixed solvent of THF (8 mL) and MeOH (4 mL). -([1,1'-biphenyl] -4-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (300 mg, 0.42 mmol) in NaOH (184 mg, 4 mL, 4 mL) in water (2 mL). .20 mmol) solution was added. The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (103 mg, 45%).
MS (ESI, pos.ion) m / z: 552.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 552.2221 [M + H] ⁺ , (C ₃₂ H ₂₈ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical value: 552.221;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.31 (s, 1H), 8.58 (d, J = 7.7 Hz, 1H), 8.31 (d, J = 10. 0 Hz, 2H), 8.18 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 5.9 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 7.41 (t, J = 7.1 Hz, 1H), 4.76 (s) , 1H), 2.93 (d, J = 6.0 Hz, 1H), 2.03 (s, 2H), 1.90-1.74 (m, 3H), 1.52 (m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.007, 157.52, 157.43, 157.30, 154.91, 152.99, 152.86, 151.95, 146. 43, 144.74, 144.68, 142.89, 141.88, 140.31, 139.87, 139.62, 133.69, 133.64, 131.90, 131.61, 131.30, 130.06, 129.60, 129.54, 129.48, 128.35, 127.24, 125.35, 118.86, 118.79, 115.55, 115.33, 114.42, 114. 38, 40.44, 40.23, 40.02, 39.81, 39.60, 30.89.

  Example 51: (+/−)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl- 1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/-)-trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (0.50 g, 1.44 mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (0.18 g, 1.44 mmol), potassium acetate (0 .42 g, 4.31 mmol) and Pd (dppf) Cl ₂ (0.13 g, 0.14 mmol) were added, followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (190 mg, 34%).
MS (ESI, pos.ion) m / z: 394.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazole- 4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) was added 5-fluoro-3- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (422 mg, 0.61 mmol, 60%), potassium carbonate (280 mg, 2.03 mmol), palladium acetate (22 mg, 0.10 mmol), XPhos (100 mg, 0.20 mmol) and 3-((2-chloro-5-fluoro-6- (1-methyl-1H-pyrazo) 4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.51 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (280 mg, 85%).
MS (ESI, pos.ion) m / z: 648.3 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl- 1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-) in a mixed solvent of THF (8 mL) and MeOH (4 mL). Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (280 mg, 0.43 mmol) in a solution of NaOH (172 mg, 4.30 mmol) in water (2 mL). ) Was added. After the mixture was stirred at rt overnight, water (10 mL) was added. The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (180 mg, 87%).
MS (ESI, pos.ion) m / z: 480.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 480.1964 [M + H] ⁺ , (C ₂₄ H ₂₄ F ₂ N ₇ O ₂ ) [M + H] ⁺ Theoretical value: 480.1960;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (s, 1 H), 8.56 (dd, J = 9.6, 2.4 Hz, 1 H), 8.39 (s, 1H), 8.35-8.25 (m, 2H), 8.10 (s, 1H), 7.48 (d, J = 6.5 Hz, 1H), 4.71 (s, 1H), 3 .97 (s, 3H), 2.89 (d, J = 6.5 Hz, 1H), 2.01 (d, J = 10.8 Hz, 2H), 1.79 (m, 3H), 1.56 (M, 4H), 1.19 (s, 2H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.006, 157.51, 154.90, 152.16, 146.40, 140.65, 139.00, 131.99, 131. 79, 131.27, 130.04, 125.35, 118.75, 116.78, 115.61, 115.40, 114.45, 51.00, 40.42, 40.21, 40.00, 39.79, 39.58, 28.84.

  Example 52: (+/−)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -Trans-methyl acetonitrile (25 mL) to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -Trans-methyl (0.50 g, 1.44 mmol), p-methoxyphenylboronic acid (0.22 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd (dppf) Cl ₂ (0 .13 g, 0.14 mmol) was added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (200 mg, 33%).
MS (ESI, pos.ion) m / z: 420.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (363 mg, 0.52 mmol, 60%), potassium carbonate (263 mg, 1.90 mmol) , Palladium acetate (21 mg, 0.09 mmol), XPhos (100 mg, 0.20 mmol) and 3-((2-chloro-5-fluoro-6- (4-methoxyphenyl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.47 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (230 mg, 72%).
MS (ESI, pos.ion) m / z: 674.2 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-) in THF / MeOH (v / v = 8 mL / 4 mL)) Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2 To a solution of carboxylic acid (+/−)-trans-methyl (230 mg, 0.34 mmol) was added a solution of sodium hydroxide (136 mg, 3.40 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (130 mg, 75% ).
MS (ESI, pos.ion) m / z: 506.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 506.2014 [M + H] ⁺ , (C ₂₇ H ₂₆ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical value: 506.2004;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.30 (s, 2H), 8 .07 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 4.73 (s, 1H), 3.85 (s, 3H), 2.90 (d, J = 5.0 Hz, 1H), 2.02 (s, 2H), 1.80 (d, J = 9.9 Hz, 3H) 1.70-1.42 (m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.006, 161.00, 157.22, 154.89, 152.91, 152.81, 151.92, 146.41, 139. 61, 131.84, 131.55, 131.19, 130.56, 130.50, 128.48, 126.89, 125.35, 118.86, 115.53, 114.48, 55.74, 40.42, 40.22, 40.01, 39.80, 39.59, 30.88.

  Example 53: (+/-)-trans-3-((6- (4- (tert-butyl) phenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine) -3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((6- (4- (tert-butyl) phenyl) -2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( +/−)-trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( +/-)-trans-methyl (0.50 g, 1.44 mmol), (4- (tert-butyl) phenyl) boronic acid (0.26 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) ) And Pd (dppf) Cl ₂ (0.13 g, 0.14 mmol) were added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (180 mg, 28%).
MS (ESI, pos.ion) m / z: 446.2 [M + H] ^< +>.

Step 2: 3-((6- (4- (tert-butyl) phenyl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (308 mg, 0.44 mmol, 60%), potassium carbonate (223 mg, 1.61 mmol), palladium acetate (18 mg, 0.08 mmol), XPhos (76 mg, 0.16 mmol) and 3-((6- (4- (tert-butyl) phenyl) -2-chloro-5-fluoro Ropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (180 mg, 0.40 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. under nitrogen protection and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (110 mg, 39%).

Step 3: (+/-)-trans-3-((6- (4- (tert-butyl) phenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine) -3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (4- (Tert-Butyl) phenyl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (110 mg, 0.16 mmol) was added a solution of sodium hydroxide (62 mg, 1.60 mmol) in water (1 mL). Added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (51 mg, 61% ).
MS (ESI, pos.ion) m / z: 532.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 532.2523 [M + H] ⁺ , (C ₃₀ H ₃₂ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical value: 532.2524;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.52 (s, 1 H), 12.27 (s, 1 H), 8.70 (dd, J = 9.7, 2.5 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J = 8.2 Hz, 2H), 8.24 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H) 7.54 (d, J = 6.6 Hz, 1H), 4.69 (t, J = 6.6 Hz, 1H), 2.88 (d, J = 6.9 Hz, 1H), 2.01 ( s, 1H), 1.95 (s, 1H), 1.84-1.72 (m, 3H), 1.64-1.40 (m, 5H), 1.34 (s, 9H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.11, 158.23, 155.11, 153.03, 151.94, 145.84, 139.65, 135.85, 133. 10, 132.59, 132.40, 132.14, 132.03, 128.49, 127.75, 125.81, 125.37, 118.81, 116.27, 108.31, 50.90, 48.00, 40.24, 40.10, 39.96, 39.82, 39.68, 34.84, 31.52, 30.88.

  Example 54: (+/-)-trans-3-((6- (benzofuran-2-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((6- (Benzofuran-2-yl) -2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl (0.50 g, 1.44 mmol), benzofuran-2-ylboronic acid (0.23 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd (dppf) Cl ₂ ( 0.13 g, 0.14 mmol) was added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (230 mg, 37%).
MS (ESI, pos.ion) m / z: 430.2 [M + H] ^< +>.

Step 2: 3-((6- (Benzofuran-2-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (445 mg, 0.64 mmol, 60%), potassium carbonate (300 mg, 2.14 mmol) ), Palladium acetate (24 mg, 0.10 mmol), XPhos (102 mg, 0.20 mmol) and 3-((6- (benzofuran-2-yl) -2-chloro-5-fluoropyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (230 mg, 0.54 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 110 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (180 mg 49%).

Step 3: (+/-)-trans-3-((6- (benzofuran-2-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (benzofuran-2-yl) in THF / MeOH (v / v = 8 mL / 4 mL)) ) -5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (+/-)-trans-methyl (180 mg, 0.26 mmol) was added a solution of sodium hydroxide (105 mg, 2.63 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (91 mg, 67%).
MS (ESI, pos.ion) m / z: 516.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 516.1845 [M + H] ⁺ , (C ₂₈ H ₂₄ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical: 516.1847;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.35 (s, 1H), 8.62 (dd, J = 9.7, 2.5 Hz, 1H), 8.38-8. 29 (m, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 6.5 Hz, 1H), 7.78-7.72 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 4.74 (s, 1H), 2.92 (d, J = 6.4 Hz) , 1H), 2.06-1.98 (m, 2H), 1.80 (m, 3H), 1.64-1.36 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.04, 155.35, 155.09, 152.73, 151.93, 150.50, 146.40, 139.64, 131. 50, 128.49, 128.24, 126.63, 125.37, 124.03, 122.68, 118.85, 118.80, 115.64, 115.50, 112.08, 110.33, 110.27, 40.24, 40.10, 39.96, 39.82, 39.68, 30.87.

  Example 55: (+/-)-trans-3-((6- (benzo [b] thiophen-2-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((6- (Benzo [b] thiophen-2-yl) -2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl acetonitrile (25 mL) to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (0.50 g, 1.44 mmol), benzo [b] thiophen-2-ylboronic acid (0.25 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) And Pd (dppf) Cl ₂ (0.13 g, 0.14 mmol) were added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (300 mg, 47%).
MS (ESI, pos.ion) m / z: 446.0 [M + H] ^< +>.

Step 2: 3-((6- (Benzo [b] thiophen-2-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (513 mg, 0.74 mmol, 60%), potassium carbonate (371 mg) 2.69 mmol), palladium acetate (30 mg, 0.13 mmol), XPhos (128 mg, 0.26 mmol) and 3-((6- (benzo [b] thiophen-2-yl) -2-chloro-5-fur. Olopyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (300 mg, 0.67 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (200 mg, 42%).

Step 3: (+/-)-trans-3-((6- (benzo [b] thiophen-2-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (Benzo) in THF / MeOH (v / v = 8 mL / 4 mL) [B] Thiophen-2-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo To a solution of [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.28 mmol) sodium hydroxide (114 mg, 2.80 mmol) in water (1 mL). The solution was added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (91 mg, 60% ).
MS (ESI, pos.ion) m / z: 532.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 532.1608 [M + H] ⁺ , (C ₂₈ H ₂₄ F ₂ N ₅ O ₂ S) [M + H] ⁺ Theoretical value: 532.1619;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.34 (s, 1H), 8.63 (dd, J = 9.6, 2.4 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.13-8.08 (m, 1H), 8.05-8.00 (m, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.49-7.43 (m, 2H), 4.72 (s, 1H), 2.90 (d, J = 6. 4 Hz, 1H), 2.02 (d, J = 9.4 Hz, 2H), 1.87-1.75 (m, 3H), 1.65-1.42 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.07, 155.37, 151.94, 146.43, 140.73, 139.65, 131.47, 128.50, 126. 35, 125.37, 125.27, 123.00, 119.13, 118.75, 118.72, 118.70, 115.54, 115.47, 115.40, 114.32, 113.87, 113.84, 40.25, 40.11, 39.97, 39.83, 39.69, 30.88.

  Example 56: (+/-)-trans-3-((6- (4-cyanophenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-6- (4-cyanophenyl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -Trans-methyl acetonitrile (25 mL) to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) -Trans-methyl (0.50 g, 1.44 mmol), (4-cyanophenyl) boronic acid (0.22 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd (dppf) Cl ₂ (0.13 g, 0.14 mmol) was added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (250 mg, 42%).
MS (ESI, pos.ion) m / z: 415.1 [M + H] ^< +>.

Step 2: 3-((6- (4-Cyanophenyl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (460 mg, 0.66 mmol, 60%), potassium carbonate (333 mg, 2.41 mmol) , Palladium acetate (27 mg, 0.12 mmol), XPhos (114 mg, 0.24 mmol) and 3-((2-chloro-6- (4-cyanophenyl) -5-fluoropyrimidin-4-yl) a Mino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (250 mg, 0.60 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (250 mg, 62%).

Step 3: (+/-)-trans-3-((6- (4-cyanophenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (4-cyanophenyl)-in THF / MeOH (v / v = 8 mL / 4 mL)) 5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2 To a solution of carboxylic acid (+/−)-trans-methyl (250 mg, 0.37 mmol) was added a solution of sodium hydroxide (149 mg, 3.70 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid to pH about 3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (120 mg, 64% ).
MS (ESI, pos.ion) m / z: 501.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 501.1846 [M + H] ⁺ , (C ₂₇ H ₂₃ F ₂ N ₆ O ₂ ) [M + H] ⁺ Theoretical value: 501.1851;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.31 (s, 1H), 8.50 (dd, J = 9.5, 2.2 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7. 76 (d, J = 6.2 Hz, 1H), 4.75 (s, 1H), 2.92 (d, J = 6.2 Hz, 1H), 2.02 (d, J = 11.4 Hz, 2H) ), 1.80 (m, 3H), 1.69-1.40 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.05, 157.69, 157.64, 156.89, 155.29, 153.00, 152.92, 151.93, 146. 38, 140.98, 139.64, 139.06, 139.03, 132.96, 131.72, 131.55, 129.83, 129.79, 128.49, 125.37, 119.09, 112.65, 40.24, 40.10, 39.96, 39.82, 39.68, 30.87.

  Example 57: (+/-)-trans-3-((6- (3,4-difluorophenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3 -Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-6- (3,4-difluorophenyl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / -)-Trans-methyl (0.50 g, 1.44 mmol), (3,4-difluorophenyl) boronic acid (0.23 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd ( After adding dppf) Cl ₂ (0.13 g, 0.14 mmol), water (1 mL) was added to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (290 mg, 47%).
MS (ESI, pos.ion) m / z: 426.1 [M + H] ^< +>.

Step 2: 3-((6- (3,4-Difluorophenyl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) was added 5-fluoro-3- (4,4,5,5). -Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (520 mg, 0.74 mmol, 60%), potassium carbonate (376 mg, 2. 72 mmol), palladium acetate (30 mg, 0.14 mmol), XPhos (130 mg, 0.28 mmol) and 3-((2-chloro-6- (3,4-difluorophenyl) -5-fluoropyrimidi N-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (290 mg, 0.68 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (240 mg, 52%).
MS (ESI, pos.ion) m / z: 680.1 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((6- (3,4-difluorophenyl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridine-3 -Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6- (3,4-) in THF / MeOH (v / v = 8 mL / 4 mL)) Difluorophenyl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2 To a solution of octane-2-carboxylic acid (+/−)-trans-methyl (240 mg, 0.35 mmol) was added a solution of sodium hydroxide (141 mg, 3.40 mmol) in water (1 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (97 mg, 54% ).
MS (ESI, pos.ion) m / z: 512.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 512.699 [M + H] ⁺ , (C ₂₆ H ₂₂ F ₄ N ₅ O ₂ ) [M + H] ⁺ Theoretical value: 512.710;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.30 (s, 1H), 8.51 (dd, J = 9.7, 2.5 Hz, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.28 (s, 1H), 8.10 (dd, J = 10.1, 8.5 Hz, 1H), 7.93 (s, 1H), 7.70 ( d, J = 6.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 4.74 (t, J = 6.1 Hz, 1H), 2.92 (d, J = 6) .6 Hz, 1H), 2.02 (d, J = 12.5 Hz, 2H), 1.87-1.73 (m, 3H), 1.69-1.40 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.04, 158.28, 157.52, 157.46, 157.03, 156.88, 155.29, 152.99, 152. 90, 151.93, 146.39, 140.60, 139.64, 131.63, 128.49, 126.29, 125.36, 118.72, 118.29, 118.17, 114.11, 40.23, 40.09, 39.95, 39.81, 39.68, 30.86.

  Example 58: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (furan-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl acetonitrile with (+/-)-trans-methyl-3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (0.50 g, 1.44 mmol), furan-3-ylboronic acid (0.16 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd (dppf) Cl ₂ (0.13 g 0.14 mmol), and then water (1 mL) was added to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (140 mg, 30%).
MS (ESI, pos.ion) m / z: 380.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (442 mg, 0.63 mmol, 60%), potassium carbonate (203 mg, 1.46 mmol) ), Palladium acetate (16 mg, 0.07 mmol), XPhos (70 mg, 0.14 mmol) and 3-((2-chloro-5-fluoro-6- (furan-3-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (140 mg, 0.36 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (198 mg, 85%).
MS (ESI, pos.ion) m / z: 634.2 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5) in THF / MeOH (v / v = 8 mL / 4 mL) -Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (+/-)-trans-methyl (198 mg, 0.31 mmol) was added a solution of sodium hydroxide (125 mg, 3.10 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (130 mg, 89% ).
MS (ESI, pos.ion) m / z: 466.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 466.1689 [M + H] ⁺ , (C ₂₄ H ₂₂ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical: 466.1691;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1 H), 8.54 (dd, J = 9.6, 2.1 Hz, 1 H), 8.40 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.57 (d, J = 6.4 Hz, 1H) 7.16 (s, 1H), 4.72 (s, 1H), 2.89 (d, J = 6.4 Hz, 1H), 2.00 (d, J = 12.4 Hz, 2H), 1 .79 (m, 3H), 1.51 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.07, 157.61, 156.88, 155.29, 152.23, 151.93, 146.39, 144.92, 144. 61, 139.64, 131.47, 128.50, 125.37, 121.30, 118.72, 115.52, 114.24, 109.92, 55.36, 51.03, 48.15, 34.83, 30.87, 28.81.

  Example 59: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4- (tri Fluoromethyl) phenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( +/−)-trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( +/-)-trans-methyl (0.50 g, 1.44 mmol), (4- (trifluoromethyl) phenyl) boronic acid (0.27 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) ) And Pd (dppf) Cl ₂ (0.13 g, 0.14 mmol) were added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (230 mg, 45%).
MS (ESI, pos.ion) m / z: 458.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4- (trifluoromethyl) phenyl ) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (383 mg, 0.55 mmol, 60%), potassium carbonate (277 mg, 2.01 mmol), palladium acetate (22 mg, 0.10 mmol), XPhos (95 mg, 0.20 mmol) and 3-((2-chloro-5-fluoro-6- (4- (trifluoromethyl) phenol). Nyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (230 mg, 0.50 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (180 mg, 50%).

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4- (tri Fluoromethyl) phenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2) in THF / MeOH (v / v = 8 mL / 4 mL) -(5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4- (trifluoromethyl) phenyl) pyrimidin-4-yl) amino) bicyclo [2 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (180 mg, 0.25 mmol) was added a solution of sodium hydroxide (101 mg, 2.50 mmol) in water (2 mL). Added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (90 mg, 65%).
MS (ESI, pos.ion) m / z: 544.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 544.1770 [M + H] ⁺ , (C ₂₆ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 544.1777;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.54 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 7. 9 Hz, 2H), 8.35 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 6.1 Hz, 1H), 4.68 (s, 1H), 2.87 (d, J = 6.2 Hz, 1H), 2.00 (s, 1H), 1.93 (s, 1H), 1.76 (m) , 3H), 1.49 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 176.12, 156.79, 155.12, 152.12, 145.84, 143.49, 142.22, 142.02, 140. 30, 132.67, 132.47, 132.37, 132.27, 130.27, 126.04, 125.88, 124.21, 118.69, 116.05, 108.45, 51.04, 48.07, 28.81, 25.82, 24.30, 21.58.

  Example 60: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (p-tolyl)) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (p-tolyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)- Trans-methyl acetonitrile (25 mL) was added to (+/-)-trans-methyl-3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane- 2-carboxylic acid (0.50 g, 1.44 mmol), p-methylphenylboronic acid (0.20 g, 1.44 mmol), potassium acetate (0.42 g, 4.31 mmol) and Pd (dppf) Cl ₂ (0 .13 g, 0.14 mmol) was added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (300 mg, 52%).
MS (ESI, pos.ion) m / z: 404.2 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (p-tolyl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) and 5-fluoro-3- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (550 mg, 0.81 mmol, 60%), potassium carbonate (410 mg, 2.97 mmol), Palladium acetate (33 mg, 0.14 mmol), XPhos (141 mg, 0.28 mmol) and 3-((2-chloro-5-fluoro-6- (p-tolyl) pyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid (+/-)-trans-methyl (300 mg, 0.74 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (300 mg, 61%).
MS (ESI, pos.ion) m / z: 658.1 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (p-tolyl)) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-fluoro) in THF / MeOH (v / v = 8 mL / 4 mL) -1-Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (p-tolyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid To a solution of acid (+/−)-trans-methyl (300 mg, 0.45 mmol) was added a solution of sodium hydroxide (182 mg, 4.50 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (140 mg, 63% ).
MS (ESI, pos.ion) m / z: 490.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 490.0503 [M + H] ⁺ , (C ₂₇ H ₂₆ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 490.055;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.27 (s, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.29 (s, 2H), 7 .97 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 5.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 4.74 (s, 1H), 2.91 (d, J = 5.6 Hz, 1H), 2.00 (d, J = 15.6 Hz, 2H), 1.88-1.73 (m, 3H), 1.53 ( m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.006, 157.33, 154.90, 152.94, 151.93, 146.42, 145.13, 142.66, 139. 98, 139.59, 131.84, 131.19, 129.59, 128.92, 128.86, 125.34, 118.88, 118.81, 115.56, 115.34, 114.42, 51.17, 48.26, 34.80, 30.86, 28.84, 21.39, 19.50.

  Example 61: (R) -3-((5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) -4,4-dimethylpentanoic acid

Step 1: 3-((2,6-Dichloro-5-fluoropyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl Into a reaction flask, 2,4,6-trichloro-5 -Fluoropyrimidine (0.64 g, 3.16 mmol), DIPEA (1.02 g, 7.91 mmol), 3-amino-4,4-dimethylpentanoic acid (R) -methyl (0.42 g, 2.63 mmol) and Dichloromethane (10 mL) was added. The mixture was stirred at rt for 24 h. After the reaction was complete, water (20 mL) was added to the mixture. The resulting mixture was extracted with DCM (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous Na ₂ SO _{4 and} concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc (v / v = 20/1) to give the title compound as a pale yellow solid (420 mg, 49%).
MS (ESI, pos.ion) m / z: 324.10 [M + H] ^< +>.

Step 2: 3-((2-Chloro-5-fluoro-6- (furan-2-yl) pyrimidin-4-yl) amino) 4,4-dimethylpentanoic acid (R) -methyl acetonitrile (25 mL) 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (420 mg, 1.29 mmol), furan-2-ylboronic acid (145 mg , 1.29 mmol), potassium acetate (381 mg, 3.88 mmol) and Pd (dppf) Cl ₂ (105 mg, 0.13 mmol) were added followed by water (1 mL). The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (180 mg, 39%).
MS (ESI, pos.ion) m / z: 356.2 [M + H] ^< +>.

Step 3: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl in THF (10 mL) and 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane. -2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (386 mg, 0.56 mmol, 60%), potassium carbonate (280 mg, 2.02 mmol), palladium acetate (22 mg, 0.10 mmol) ), XPhos (100 mg, 0.20 mmol) and 3-((2-chloro-5-fluoro-6- (furan-2-yl) pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid ( R) -Methyl (180 mg, 0.50 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the mixture was heated to 100 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (230 mg, 74%).
MS (ESI, pos.ion) m / z: 610.2 [M + H] ^< +>.

Step 4: (R) -3-((5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) -4,4-dimethylpentanoic acid 3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo) in THF / MeOH (v / v = 8 mL / 4 mL) [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (230 mg, 0.37 mmol) ) Was added a solution of sodium hydroxide (150 mg, 3.70 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (20 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (110 mg, 66%).
MS (ESI, pos.ion) m / z: 442.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 442.1687 [M + H] ⁺ , (C ₂₂ H ₂₂ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical value: 442.1691;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (s, 1H), 12.05 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8 .29 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 4.84 (t, J = 8.4 Hz, 1H), 2.73-2.56 (m, 2H), 0.99 (s, 9H).

  Example 62: (+/−)-trans-3-((6- (dibenzo [b, d] furan-4-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3- b] Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-6- (dibenzo [b, d] furan-4-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/-)-trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (0.40 g, 1.15 mmol), dibenzo [b, d] furan-4-ylboronic acid (0.244 g, 1.15 mmol), potassium acetate (0.33 g, 3.45 mmol) and Pd (dppf) Cl ₂ (0.09 g, 0.11 mmol) were added, followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (170 mg, 31%).
MS (ESI, pos.ion) m / z: 480.1 [M + H] ^< +>.

Step 2: 3-((6- (Dibenzo [b, d] furan-4-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine- 3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) was added 5-fluoro-3- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (286 mg, 0.41 mmol, 60%), potassium carbonate (207 mg, 1.50 mmol), palladium acetate (16 mg, 0.07 mmol), XPhos (71 mg, 0.14 mmol) and 3-((2-chloro-6- (dibenzo [b, d] furan-4-yl) -5-F Fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (180 mg, 0.37 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (200 mg, 73%).
MS (ESI, pos.ion) m / z: 734.1 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((6- (dibenzo [b, d] furan-4-yl) -5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3- b] Pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((6-) in THF / MeOH (v / v = 8 mL / 4 mL) (Dibenzo [b, d] furan-4-yl) -5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.27 mmol) in sodium hydroxide (109 mg, 2 mL) in water (1 mL). .72 mmol) solution was added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (130 mg, 84% ).
MS (ESI, pos.ion) m / z: 566.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 56.6.1982 [M + H] ⁺ , (C ₃₂ H ₂₆ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical: 56.6.2004;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.30 (s, 1H), 8.61 (d, J = 8.3 Hz, 1H), 8.29 (s, 3H), 8 .22 (d, J = 6.5 Hz, 1H), 7.91 (d, J = 6.3 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.64-7.51 (m, 2H), 7.44 (s, 1H), 4.80 (s, 1H), 2.93 (s, 1H), 2.06 (s, 2H) ), 1.65 (m, 8H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.08, 157.96, 157.88, 156.03, 154.95, 153.30, 152.53, 152.41, 151. 93, 146.43, 143.29, 143.18, 140.09, 139.61, 131.96, 131.67, 131.26, 128.61, 128.48, 128.43, 125.35, 124.73, 123.76, 122.95, 121.77, 119.62, 118.95, 118.87, 115.68, 115.46, 114.33, 112.13, 51.22, 48. 25, 34.80, 30.87, 28.83, 28.75, 22.30, 22.04.

  Example 63: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylethynyl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 2,4-Dichloro-5-fluoro-6- (phenylethynyl) pyrimidine In THF (20 mL), 2,4,6-trichloro-5-fluoropyrimidine (1.00 g, 4.96 mmol), iodinated Cuprous (0.19 g, 9.92 mmol), bis (triphenylphosphine) palladium (II) chloride (0.35 g, 0.49 mmol) and triethylamine (1.51 g, 14.9 mmol) were added. Then phenylacetylene (0.48 g, 4.70 mmol) was slowly added dropwise to the mixture under nitrogen protection and the mixture was stirred at rt for 4 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a yellow solid (550 mg, 42%).
MS (ESI, pos.ion) m / z: 266.9 [M + H] ^< +>.

Step 2: 3-((2-Chloro-5-fluoro-6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans -Methyl Reaction flask was charged with 2,4-dichloro-5-fluoro-6- (phenylethynyl) pyrimidine (0.55 g, 2.05 mmol), DIPEA (0.53 g, 4.11 mmol), 3-aminobicyclo [2 2.2.2] Octane-2-carboxylic acid (+/-)-trans-methyl (0.46 g, 2.47 mmol) and DCM (10 mL) were added. The mixture was stirred at rt for 18 h. After the reaction was complete, water (20 mL) was added to the reaction mixture and the resulting mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (0.58 g, 68%). ).
MS (ESI, pos.ion) m / z: 414.3 [M + H] ^< +>.

Step 3: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylethynyl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (400 mg, 0.58 mmol, 60%), potassium carbonate (267 mg, 1.93 mmol), palladium acetate (21 mg, 0.09 mmol), XPhos (92 mg, 0.18 mmol) and 3-((2-chloro-5-fluoro-6- (phenylethynyl) pyrimidin-4-yl) amino) bi Cyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (200 mg, 0.48 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (162 mg, 50%).

Step 4: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (phenylethynyl) pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (5-fluoro-) in THF / MeOH (v / v = 8 mL / 4 mL) 1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( To a solution of +/−)-trans-methyl (162 mg, 0.24 mmol) was added a solution of sodium hydroxide (97 mg, 2.40 mmol) in water (2 mL). The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (99 mg, 82%).
MS (ESI, pos.ion) m / z: 500.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 500.1892 [M + H] ⁺ , (C ₂₈ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical value: 500.1898;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.32 (s, 1H), 8.51 (dd, J = 9.6, 2.2 Hz, 1H), 8.31-8. 25 (m, 2H), 7.80 (d, J = 6.6 Hz, 1H), 7.70-7.64 (m, 2H), 7.50 (d, J = 6.7 Hz, 3H), 4.74 (s, 1H), 2.90 (d, J = 6.4 Hz, 1H), 2.03 (s, 1H), 1.98 (s, 1H), 1.80 (m, 3H) 1.69-1.41 (m, 5H).

  Example 64: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl- 1H-pyrrol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-5-fluoro-6- (1-methyl-1H-pyrrol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/-)-trans-methyl acetonitrile (25 mL) was added to 3-((2,6-dichloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl (0.40 g, 1.14 mmol), (1-methyl-1H-pyrrol-3-yl) boronic acid (0.23 g, 1.14 mmol), potassium acetate (0 .34 g, 3.46 mmol) and Pd (dppf) Cl ₂ (0.09 g, 0.11 mmol) were added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (150 mg, 33%).
MS (ESI, pos.ion) m / z: 393.1 [M + H] ^< +>.

Step 2: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-1-methyl-1H-pyrrole-3 -Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in THF (10 mL) to 5-fluoro-3- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (423 mg, 0.46 mmol, 45%), potassium carbonate ( 211 mg, 1.52 mmol), palladium acetate (17 mg, 0.07 mmol), XPhos (72 mg, 0.14 mmol) and 3-((2-chloro-5-fluoro-6- (1-methyl-1H-pyrrole-3) -Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (150 mg, 0.38 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (230 mg 93%).
MS (ESI, pos.ion) m / z: 647.1 [M + H] ^< +>.

Step 3: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl- 1H-pyrrol-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-) in THF / MeOH (v / v = 8 mL / 4 mL) Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (1-methyl-1H-pyrrol-3-yl) pyrimidin-4-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (230 mg, 0.35 mmol) in sodium hydroxide (142 mg, 3 mL) in water (2 mL). .55 mmol) solution was added. The mixture was stirred at rt overnight. Water (10 mL) was added to the reaction mixture and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜3-4. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (120 mg, 71%).
MS (ESI, pos.ion) m / z: 479.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 479.2024 [M + H] ⁺ , (C ₂₆ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical value: 479.2007;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.21 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.27 (s, 2H), 7 .52 (s, 1H), 7.28 (d, J = 4.1 Hz, 1H), 6.87 (s, 2H), 4.69 (s, 1H), 3.74 (s, 3H), 2.87 (d, J = 3.9 Hz, 1H), 2.00 (s, 2H), 1.80 (m, 3H), 1.67-1.45 (m, 5H).

  Example 65: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a microwave tube, 5-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (347 mg, 0.50 mmol, 60%), 3-((2-chloro- 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (146 mg, 0. 41 mmol), potassium carbonate (114 mg,. 82 mmol), Pd (dppf) Cl ₂ (30 mg, 0.04 mmol), 1,4-dioxane (5 mL) and water (0.5 mL) were added. After the air in the mixture was removed by bubbling with nitrogen for 10 min, the mixture in the microwave tube was stirred at 110 ° C. for 2 h while being heated by microwave. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (214 mg, 56%) .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.75 (dd, J = 9.0, 2.8 Hz, 1H), 8.67 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 6.1 Hz, 2H), 6.92 (d, J = 3.4 Hz, 1H) ), 6.38 (d, J = 3.3 Hz, 1H), 5.13 (d, J = 6.9 Hz, 1H), 4.90 (d, J = 5.9 Hz, 1H), 3.86 (S, 3H), 3.75 (s, 3H), 2.48 (d, J = 5.6 Hz, 1H), 2.37 (s, 3H), 2.07 (d, J = 2.0 Hz) , 2H), 2.01 (s, 1H), 1.94 (m, 1H), 1.79 (m, 8H).

Step 2: (+/-)-trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3 -D] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2-) in a mixed solvent of THF and MeOH (v / v = 1/1, 6 mL). (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [ 2.2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (197 mg, 0.33 mmol) was added aqueous sodium hydroxide (4 M, 0.90 mL, 3.60 mmol). . The mixture was stirred at 30 ° C. overnight. Water (10 mL) was added to the reaction mixture, and the resulting mixture was acidified with hydrochloric acid (1M) to pH ˜5.5. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (80 mg, 56%).
MS (ESI, pos.ion) m / z: 435.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 435.1941 [M + H] ⁺ , (C ₂₃ H ₂₄ FN ₆ O ₂ ) [M + H] ⁺ Theoretical value: 435.1945;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1 H), 12.09 (s, 1 H), 8.73 (d, J = 8.5 Hz, 1 H), 8 .27 (s, 1H), 8.24 (s, 1H), 7.22 (d, J = 5.7 Hz, 1H), 7.08 (s, 1H), 6.62 (s, 1H), 4.80 (s, 1H), 3.78 (s, 3H), 2.72 (d, J = 5.7 Hz, 1H), 2.03 (d, J = 15.2 Hz, 2H), 1. 80 (m, 3H), 1.49 (m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.22, 157.13, 156.03, 154.75, 150.65, 146.43, 131.51, 131.22, 130. 00, 124.76, 119.07, 118.99, 116.07, 115.99, 115.95, 115.86, 101.15, 98.95, 50.63, 49.11, 31.05, 28.98, 28.87, 26.09, 24.23, 21.59, 19.52.

  Example 66: (+/-)-trans-3-((5- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazolo [5,4-d] pyrimidine-7- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((5-chlorothiazolo [5,4-d] pyrimidin-7-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 3- Aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (284 mg, 1.55 mmol) and 5,7-dichlorothiazolo [5,4-d] pyrimidine (352 mg, After 1.71 mmol) was dissolved in DMF (5 mL), potassium carbonate (428 mg, 3.10 mmol) was added. The mixture was stirred at rt overnight. The reaction was stopped and water (50 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (317 mg, 58%).
MS (ESI, pos.ion) m / z: 353.0 [M + H] ⁺ ;
¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.75 (s, 1H), 6.49 (d, J = 4.7 Hz, 1H), 4.63 (s, 1H), 3.76 (S, 3H), 2.50 (d, J = 5.6 Hz, 1H), 2.01 (d, J = 1.8 Hz, 1H), 1.95 (d, J = 2.5 Hz, 1H) 1.88-1.76 (m, 2H), 1.73-1.53 (m, 6H).

Step 2: 3-((5- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazolo [5,4-d] pyrimidin-7-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (180 mg, 0.21 mmol, 50%), K ₂ CO ₃ (39 mg, 0.28 mmol) , PdCl ₂ (dppf) (8 mg, 0.01 mmol) and 3-((5-chlorothiazolo [5,4-d] pyrimidin-7-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-Tran S-methyl (51 mg, 0.14 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 2 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (61 mg, 70% ).

Step 3: (+/-)-trans-3-((5- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) thiazolo [5,4-d] pyrimidine-7- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid To a mixed solvent of THF and MeOH (v / v = 2 mL / 2 mL), 3-((5- (5-fluoro-1-tosyl- 1H-pyrrolo [2,3-b] pyridin-3-yl) thiazolo [5,4-d] pyrimidin-7-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl (61 mg, 0.10 mmol) was added followed by a solution of NaOH (40 mg, 1.00 mmol) in water (1 mL). The resulting mixture was stirred at rt overnight before water (10 mL) was added. The mixture was acidified with hydrochloric acid (1M) to pH ˜6 and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid (16 mg, 36% ).
MS (ESI, pos.ion) m / z: 439.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 439.1329, (C 21 H 20 FN 6 O 2 S) [M + H] + Calculated: 439.1352;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.38 (s, 1H), 9.13 (s, 1H), 8.63 (d, J = 9.4 Hz, 1H), 8 .35 (s, 1H), 8.29 (s, 1H), 8.21 (d, J = 6.5 Hz, 1H), 4.89 (s, 1H), 3.03 (d, J = 5) .4 Hz, 1H), 2.03 (s, 2H), 1.83 (m, 3H), 1.70-1.43 (m, 5H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 162.39, 159.26, 155.57, 155.35, 150.28, 146.39, 132.01, 131.87, 131. 82, 128.61, 118.97, 118.92, 115.79, 115.65, 114.35, 114.32, 51.02, 47.92, 28.90, 28.77, 25.62, 24.34, 21.64, 19.59.

  Example 67: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-9-methyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 3- Aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (400 mg, 2.18 mmol) and 2,6-dichloro-9-methyl-9H-purine (400 mg, 1. 97 mmol) was dissolved in acetonitrile (8 mL), then DIPEA (1.75 mL, 9.95 mmol) was added. The mixture was stirred overnight at 50 ° C. under nitrogen protection. Water (50 mL) was added to the reaction mixture and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3/1) to give the title compound as a yellow solid (457 mg, 66%).
MS (ESI, pos.ion) m / z: 350.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.66 (s, 1H), 6.37 (s, 1H), 4.55 (s, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.21 (s, 1H), 2.43 (s, 1H), 1.94 (s, 1H), 1.88 (d, J = 2.5 Hz, 1H) 1.78 (d, J = 10.6 Hz, 2H), 1.66 to 1.44 (m, 5H).

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid (+/-)-trans-methyl 1,4-dioxane (8 mL) to 5-fluoro-3- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (540 mg, 0.52 mmol, 40%), K ₂ CO ₃ (119 mg, 0.86 mmol), PdCl ₂ (dppf) (29 mg, 0.04 mmol) and 3-((2-chloro-9-methyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ( +/-)-trans-methyl (151 mg, 0.43 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 2 h. The mixture was filtered through a celite pad to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 2/1) to give the title compound as a white solid (166 mg, 64% ).

Step 3: (+/-)-Trans-3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl ) Amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [3]) in THF / MeOH (v / v = 3 mL / 3 mL) 2,3-b] pyridin-3-yl) -9-methyl-9H-purin-6-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl To a solution of (166 mg, 0.28 mmol) was added a solution of NaOH (112 mg, 2.8 mmol) in water (2 mL). The mixture was stirred at rt overnight and then acidified to pH ˜6 with hydrochloric acid (1M). The resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (71 mg, 59%).
MS (ESI, pos.ion) m / z: 436.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 436.1874, (C 22 H 23 FN 7 O 2) [M + H] + Calculated: 436.1897;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (s, 2H), 8.70 (s, 1H), 8.25 (d, J = 10.4 Hz, 2H), 8 .06 (s, 1H), 7.67 (s, 1H), 4.83 (s, 1H), 3.79 (s, 3H), 2.95 (s, 1H), 2.00 (s, 2H), 1.84-1.74 (m, 3H), 1.50 (m, 5H);
¹³ C NMR (101 MHz, DMSO-d ₆ ) δ (ppm): 176.19, 157.22, 157.08, 154.84, 146.36, 141.10, 131.67, 131.38, 130. 58, 119.01, 118.93, 115.33, 110.00, 61.82, 50.56, 48.35, 29.69, 28.89, 25.80, 24.28, 21.63, 19.50.

  Example 68: (+/-)-trans-3-((6-cyclopropyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((2-Chloro-6-cyclopropylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl tetrahydrofuran (5 mL) Of 3-((2,6-dichloropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (100 mg, 0.30 mmol) in To the solution was added Pd (dppf) Cl ₂ (25 mg, 0.03 mmol), potassium phosphate (160 mg, 0.75 mmol) and cyclopropylboronic acid (27 mg, 0.31 mmol). The mixture was refluxed overnight under nitrogen protection. The reaction mixture was cooled to rt, concentrated in vacuo to dryness. To the residue was added ethyl acetate (20 mL) and the mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 5/1) to give the title compound as a colorless oil (59 mg, 58% ).
MS (ESI, pos.ion) m / z: 336.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.18 (s, 1H), 5.37-5.13 (m, 1H), 4.17 (d, J = 19.1 Hz, 1H) 3.76-3.73 (m, 3H), 2.35-2.31 (m, 1H), 2.07-2.03 (m, 1H), 1.84-1.79 (m, 2H), 1.70 (d, J = 7.3 Hz, 2H), 1.65 (d, J = 7.0 Hz, 2H), 1.54 (d, J = 10.7 Hz, 2H), 46 (d, J = 7.3 Hz, 1H), 1.36-1.23 (m, 1H), 1.08 (tt, J = 9.1, 4.5 Hz, 2H), 1.02-0 96 (m, 2H).

Step 2: 3-((6-Cyclopropyl-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2 2.2] Octane-2-carboxylic acid (+/-)-trans-methyl Into a microwave tube, add 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane. -2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (1.03 g, 1.49 mmol, 60%), 3-((2-chloro-6-cyclopropylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (400 mg, 1.191 mmol), water (0.5 mL), 1,4-dioxane (15 mL) , Potassium carbonate (44 2 mg, 3.20 mmol) and Pd (dppf) Cl ₂ (130 mg, 0.16 mmol) were added. Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred for 1 h at 110 ° C. with microwave heating. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 15/1) to give the title compound as a pale yellow oil (251 mg, 36%).
MS (ESI, pos.ion) m / z: 590.5 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.57 (s, 1H), 8.49 (dd, J = 9.0, 2.7 Hz, 1H), 8.32 (s, 1H) 8.30 (s, 1H), 8.10 (d, J = 6.1 Hz, 2H), 8.09 (s, 2H), 6.20 (s, 1H), 5.03 (s, 1H) ), 3.77 (s, 1H), 3.74 (s, 3H), 2.38 (s, 3H), 1.95-1.87 (m, 4H), 1.79 (s, 4H) 1.01 (dt, J = 11.3, 5.5 Hz, 4H).

Step 3: (+/-)-trans-3-((6-cyclopropyl-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid 3-((6-cyclopropyl-2- (5-fluoro-) in a mixed solvent of THF (5 mL), methanol (5 mL) and water (5 mL). 1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans- To a mixture of methyl (250 mg, 0.42 mmol) solution was added NaOH (170 mg, 4.25 mmol) in small portions. The mixture was stirred at rt overnight and concentrated in vacuo to remove the organic solvent. To the residue, water (15 mL) was added and the resulting mixture was acidified to pH ˜6 with dilute hydrochloric acid (1 mol / L). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1-10 / 1) to give the title compound as a white solid. (90 mg, 50%).
MS (ESI, pos.ion) m / z: 422.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 422.1964 [M + H] ⁺ , (C ₂₃ H ₂₆ FN ₅ O ₂ ) [M + H] ⁺ Theoretical: 422.1992;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.96 (s, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 7.26 (s, 1H) ), 7.18 (s, 1H), 7.09 (s, 1H), 6.07 (s, 1H), 4.78 (s, 1H), 2.55 (s, 1H), 2.12 (S, 1H), 2.04 (s, 1H), 1.91 (s, 1H), 1.73-1.39 (m, 8H), 1.12 (d, J = 4.3 Hz, 2H) ), 1.00 (s, 2H);
¹³ C NMR (151 MHz, DMSO-d ₆ ) δ (ppm): 175.37, 162.36, 159.01, 158.81, 157.35, 155.74, 146.17, 134.80, 133. 52, 133.33, 118.79, 118.74, 115.81, 115.67, 95.75, 51.41, 48.79, 29.07, 28.45, 25.60, 24.09, 21.50, 21.20, 19.33, 12.87, 10.50, 10.34.

  Example 69: (R) -3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid

Step 1: 3-((2,6-Dichloro-5-fluoropyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl Into a reaction flask, 2,4,6-trichloro-5 -Fluoropyrimidine (0.64 g, 3.16 mmol), DIPEA (1.02 g, 7.91 mmol), 3-amino-4,4-dimethylpentanoic acid (R) -methyl (0.42 g, 2.63 mmol) and Dichloromethane (10 mL) was added and the reaction mixture was stirred at rt for 24 h. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a pale yellow solid (420 mg, 49%).
MS (ESI, pos.ion) m / z: 324.10 [M + H] ^< +>.

Step 2: 3-((2-Chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl Acetonitrile (25 mL) was added 3-((2 , 6-Dichloro-5-fluoropyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (420 mg, 1.29 mmol), phenylboronic acid (680 mg, 2.09 mmol), potassium acetate (617 mg, 6.29 mmol) and Pd (dppf) Cl ₂ (171 mg, 0.21 mmol) were added followed by water (1 mL) to the mixture. The resulting mixture was stirred at 80 ° C. for 12 h under nitrogen protection. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20/1) to give the title compound as a yellow solid (480 mg, 63%).
MS (ESI, pos.ion) m / z: 366.2 [M + H] ^< +>.

Step 3: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4-Dimethylpentanoic acid (R) -methyl THF (10 mL) to 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1-tosyl-1H-pyrrolo [2,3-b] pyridine (695 mg, 0.75 mmol, 45%), potassium carbonate (337 mg, 2.73 mmol), palladium acetate (30 mg, 0.14 mmol), XPhos (130 mg, 0.27 mmol) and 3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (250 mg) 0.68 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the mixture was heated to 100 ° C. under nitrogen protection and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (200 mg, 47%).
MS (ESI, pos.ion) m / z: 620.2 [M + H] ^< +>.

Step 4: (R) -3-((5-Fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl)
Amino) -4,4-dimethylpentanoic acid 3-((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3]) in THF / MeOH (v / v = 8 mL / 4 mL) B) Pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (200 mg, 0.33 mmol) in water (2 mL) Of NaOH (129 mg, 3.22 mmol) was added. The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (40 mg, 27%).
MS (ESI, pos.ion) m / z: 452.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 452.1896 [M + H] ⁺ , (C ₂₄ H ₂₄ F ₂ N ₅ O ₂ ) [M + H] ⁺ Theoretical: 452.1898;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.38 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.37 (s, 1H), 8 .31 (s, 1H), 8.04 (d, J = 6.6 Hz, 2H), 7.68 (s, 1H), 7.59 (d, J = 7.5 Hz, 3H), 4.89 (S, 1H), 2.76-2.58 (m, 2H), 1.22 (s, 1H), 1.00 (s, 9H).

  Example 70: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) -4,4-dimethylpentanoic acid

Step 1: 3-((2-Chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl 2,4 in DMF (10 mL) -Dichloro-6- (furan-2-yl) pyrimidine (0.30 g, 1.40 mmol), potassium carbonate (0.39 g, 2.80 mmol), 3-amino-4,4-dimethylpentanoic acid (R)- A suspension of methyl (0.48 g, 1.80 mmol) was stirred at 80 ° C. for 24 h. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a pale white solid (300 mg, 64%).
MS (ESI, pos.ion) m / z: 338.2 [M + H] ^< +>.

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) -4,4-dimethylpentanoic acid (R) -methyl THF (10 mL) and 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1-Tosyl-1H-pyrrolo [2,3-b] pyridine (821 mg, 0.88 mmol, 45%), potassium carbonate (491 mg, 3.55 mmol), palladium acetate (39 mg, 0.17 mmol), XPhos ( 169 mg, 0.35 mmol) and 3-((2-chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (300 mg, 0 .88 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 100 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (300 mg, 57%).
MS (ESI, pos.ion) m / z: 592.2 [M + H] ^< +>.

Step 3: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) -4,4-dimethylpentanoic acid 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine) in THF / MeOH (v / v = 8 mL / 4 mL) To a solution of (3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (300 mg, 0.50 mmol), water (2 mL A solution of NaOH (202 mg, 5.07 mmol) in) was added. The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (180 mg, 83%).
MS (ESI, pos.ion) m / z: 424.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 424.1793 [M + H] ⁺ , (C ₂₂ H ₂₃ FN ₅ O ₃ ) [M + H] ⁺ Theoretical value: 414.1785;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.25 (s, 1 H), 12.05 (s, 1 H), 8.67 (d, J = 9.0 Hz, 1 H), 8 .30 (d, J = 10.6 Hz, 2H), 7.88 (s, 1H), 7.34 (d, J = 9.4 Hz, 1H), 7.23 (s, 1H), 6.70 (S, 1H), 6.66 (s, 1H), 4.82 (s, 1H), 2.68 (d, J = 12.7 Hz, 1H), 2.35-2.23 (m, 1H) ), 0.98 (s, 9H).

  Example 71: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4 -Dimethylpentanoic acid

Step 1: 3-((2-Chloro-6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl The reaction flask was charged with 2,4-dichloro-6-phenylpyrimidine (0 .30 g, 1.30 mmol), potassium carbonate (0.37 g, 2.70 mmol), 3-amino-4,4-dimethylpentanoic acid (R) -methyl (0.46 g, 1.70 mmol) and DMF (10 mL) ) Was added. The mixture was stirred at 80 ° C. for 24 h. Water (40 mL) was added and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a white solid (120 mg, 26%).
MS (ESI, pos.ion) m / z: 348.1 [M + H] ^< +>.

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4 -Dimethylpentanoic acid (R) -methyl THF (10 mL) to 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl- 1H-pyrrolo [2,3-b] pyridine (383 mg, 0.41 mmol, 45%), potassium carbonate (190 mg, 1.38 mmol), palladium acetate (15 mg, 0.07 mmol), XPhos (65 mg, 0.14 mmol) And 3-((2-chloro-6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (120 mg, 0.34 mmol) was added. . H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 100 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (180 mg, 86%).
MS (ESI, pos.ion) m / z: 602.3 [M + H] ^< +>.

Step 3: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) -4,4 -3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl)-in dimethylpentanoic acid THF / MeOH (v / v = 8 mL / 4 mL)- 6-phenylpyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (180 mg, 0.30 mmol) was added to a solution of NaOH (120 mg, 2.99 mmol) in water (2 mL). The solution was added. The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (94 mg, 72%).
MS (ESI, pos.ion) m / z: 434.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 434.2013 [M + H] ⁺ , (C ₂₄ H ₂₅ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 434.1992;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.26 (s, 1 H), 12.05 (s, 1 H), 8.70 (d, J = 9.3 Hz, 1 H), 8 .37 (s, 1H), 8.29 (s, 1H), 8.09 (d, J = 6.6 Hz, 2H), 7.54 (dt, J = 13.2, 6.8 Hz, 3H) 7.30 (d, J = 19.0 Hz, 1 H), 6.82 (s, 1 H), 4.86 (s, 1 H), 2.70 (d, J = 12.8 Hz, 1 H), 2 .38-2.24 (m, 1H), 0.99 (s, 9H).

  Example 72: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) -4,4-dimethylpentanoic acid

Step 1: 3-((2-Chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl 2,4-Dichloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine (0.30 g, 1.30 mmol), potassium carbonate (0.36 g, 2.61 mmol), 3-amino-4,4 -Dimethylpentanoic acid (R) -methyl (0.42 g, 1.56 mmol) and DMF (10 mL) were added and the mixture was stirred at 80 ° C. for 24 h. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a pale white solid (260 mg, 56%).
MS (ESI, pos.ion) m / z: 353.10 [M + H] ^< +>.

Step 2: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl THF (10 mL) was added to 5-fluoro-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (749 mg, 0.81 mmol, 45%), potassium carbonate (407 mg, 2.95 mmol), palladium acetate (33 mg, .0. 15 mmol), XPhos (140 mg, 0.30 mmol) and 3-((2-chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4,4-dimethyl Pentanoic acid (R) -methyl (260 mg, 0.74 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 100 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (310 mg, 69%).
MS (ESI, pos.ion) m / z: 607.3 [M + H] ^< +>.

Step 3: (R) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) -4,4-dimethylpentanoic acid 3-((2- (5-fluoro-1-tosyl-1H-pyrrolo [2,]) in THF / MeOH (v / v = 8 mL / 4 mL). 3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) -4,4-dimethylpentanoic acid (R) -methyl (300 mg, 0 To a solution of .49 mmol) was added a solution of NaOH (197 mg, 4.95 mmol) in water (2 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (180 mg, 83%).
MS (ESI, pos.ion) m / z: 439.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 439.2271 [M + H] ⁺ , (C ₂₃ H ₂₈ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 439.2258;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.06 (s, 1H), 11.94 (s, 1H), 8.74 (d, J = 9.4 Hz, 1H), 8 .23 (d, J = 18.8 Hz, 2H), 7.18 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 5.09-4.96 (m, 2H), 2.70 (d, J = 12.7 Hz, 1H), 1.50 (dd, J = 6.2, 3 .5 Hz, 6H), 1.24 (s, 2H), 1.00 (s, 9H).

  Example 73: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl reaction To the flask, 2,4-dichloro-6- (furan-2-yl) pyrimidine (0.50 g, 2.30 mmol), potassium carbonate (0.83 g, 6.00 mmol), 3-aminobicyclo [2.2. 2] Octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride (0.70 g, 3.00 mmol) and DMF (10 mL) were added. The mixture was stirred at 50 ° C. for 24 h. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a pale white solid (610 mg, 70%).
MS (ESI, pos.ion) m / z: 376.0 [M + H] ^< +>.

Step 3: 3-Bromo-6-fluoro-1H-pyrrolo [2,3-b] pyridine 6-Fluoro-1H-pyrrolo [2,3-b] pyridine (2.50 g, 18.) in DMF (50 mL). To a solution of 36 mmol) was added a solution of bromine (3.20 g, 20.00 mmol) in DMF (20 mL) at 0 ° C. After the addition, the mixture was stirred at rt for 2 h. After adding water (100 mL) to the mixture, many solids precipitated. The mixture was filtered under reduced pressure and the filter cake was washed twice with water (30 mL) and then vacuum dried at 60 ° C. for 24 h to give the title compound as a white solid (3.44 g, 87%).
MS (ESI, pos.ion) m / z: 217.1 [M + H] ⁺ ;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.20 (s, 1 H), 8.04-7.95 (m, 1 H), 7.67 (d, J = 2.5 Hz, 1H), 6.94 (t, J = 9.7 Hz, 1H).

Step 4: 3-Bromo-6-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine 3-Bromo-6-fluoro-1H-pyrrolo [2,3-b] in THF (68 mL) To a solution of pyridine (3.44 g, 16.00 mmol), sodium hydride (1.30 g, 32.00 mmol, 60%) was added at 0 ° C. The reaction mixture was then stirred at 0 ° C. for 30 min. TsCl (4.58 g, 24.00 mmol) was added and the reaction mixture was stirred at rt for 3 h. Water (200 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as a brown solid (5.70 g, 97%).
MS (ESI, pos.ion) m / z: 369.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.11 (d, J = 8.2 Hz, 2H), 7.88 (t, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H).

Step 5: 6-Fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine
3-Bromo-6-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridine (5.70 g, 15.00 mmol), tetrakis (triphenylphosphine) platinum in 1,4-dioxane (120 mL) To a suspension of (1.80 g, 1.50 mmol) and potassium acetate (4.50 g, 46.00 mmol) was added bis (pinacolato) diboron (5.90 g, 23.00 mmol). The mixture was stirred at 100 ° C. for 24 h under nitrogen protection. To the reaction mixture was added ethyl acetate (50 mL) and the mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (20 mL × 2). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 40/1) to give the title compound as a yellow solid (3.50 g, 54 %).
MS (ESI, pos.ion) m / z: 417.30 [M + H] ^< +>.

Step 6: 3-((2- (6-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl in THF (10 mL) and 6-fluoro-3- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (610 mg, 0.64 mmol, 45%), potassium carbonate (338 mg, 2.45 mmol), palladium acetate (27 mg , 0.12 mmol), XPhos (116 mg, 0.24 mmol) and 3-((2-chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane- 2-Carboxylic acid (2S, 3S) -ethyl (230 mg, 0.61 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (260 mg, 67%).
MS (ESI, pos.ion) m / z: 630.1 [M + H] ^< +>.

Step 7: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (6-fluoro-1-tosyl-1H-pyrrolo) in THF / MeOH (v / v = 8 mL / 4 mL) [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -To a solution of ethyl (260 mg, 0.41 mmol) was added a solution of NaOH (146 mg, 4.12 mmol) in water (2 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (150 mg, 81%).
MS (ESI, pos.ion) m / z: 448.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 448.1793 [M + H] ⁺ , (C ₂₄ H ₂₃ FN ₅ O ₃ ) [M + H] ⁺ Theoretical: 448.1785;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.21 (s, 1H), 9.00 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H) ), 7.55 (s, 1H), 7.28 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 4.59 (s, 1H), 2.51 (s, 1H), 1.94 (s, 1H), 1.80-1.71 (m, 2H), 1.68 (s, 1H) ), 1.62-1.53 (m, 3H), 1.48-1.36 (m, 3H).

  Example 74: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl in a reaction flask was 2,4-dichloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine (0.60 g, 2.61 mmol), potassium carbonate (1.01 g, 7.31 mmol), 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride (0.85 g, 3.65 mmol) and DMF (10 mL) were added and the mixture was stirred at 50 ° C. for 24 h. Stir. Water (20 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a pale white solid (732 mg, 71%).
MS (ESI, pos.ion) m / z: 391.10 [M + H] ^< +>.

Step 3: 3-((2- (6-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl in THF (10 mL) was added 6-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (580 mg, 0.56 mmol, 40%), potassium carbonate (282 mg, 2.05 mmol) , Palladium acetate (22 mg, 0.10 mmol), XPhos (97 mg, 0.20 mmol) and 3-((2-chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) a Mino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (200 mg, 0.51 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (280 mg, 84%).
MS (ESI, pos.ion) m / z: 645.3 [M + H] ^< +>.

Step 4: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d ] Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (6-fluoro-1-) in THF / MeOH (v / v = 8 mL / 4 mL) Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (2S, 3S) -ethyl (280 mg, 0.43 mmol) was added a solution of NaOH (173 mg, 4.34 mmol) in water (2 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (180 mg, 89%).
MS (ESI, pos.ion) m / z: 463.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 463.2268 [M + H] ⁺ , (C25H ₂₈ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 4633.2258;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.04 (s, 1H), 9.04 (t, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7 .22 (d, J = 6.3 Hz, 1H), 7.19 (s, 1H), 6.94 (d, J = 8.6 Hz, 1H), 6.66 (s, 1H), 5.01 (D, J = 6.6 Hz, 1H), 4.75 (s, 1H), 2.68 (s, 1H), 1.98 (s, 1H), 1.75 (m, 3H), 1. 51 (m, 11H).

  Example 75: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl -Dichloro-6-phenylpyrimidine (0.76 g, 3.40 mmol), potassium carbonate (0.93 g, 6.80 mmol), 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S ) -Ethyl hydrochloride (0.96 g, 4.10 mmol) and DMF (10 mL) were added. The mixture was stirred at 50 ° C. for 24 h. Water (40 mL) was added to quench the reaction and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 15/1) to give the title compound as a white solid (0.70 g, 50%).
MS (ESI, pos.ion) m / z: 386.1 [M + H] ^< +>.

Step 3: 3-((2- (6-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2. 2.2] Octane-2-carboxylic acid (2S, 3S) -ethyl THF (10 mL) and 6-fluoro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (503 mg, 0.54 mmol, 45%), potassium carbonate (286 mg, 2.07 mmol), palladium acetate (23 mg, 0.10 mmol), XPhos (98 mg, 0.20 mmol) and 3-((2-chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S ) -Ethyl (200 mg, 0.52 mmol) was added. H ₂ O (0.5 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (240 mg, 72%).
MS (ESI, pos.ion) m / z: 640.2 [M + H] ^< +>.

Step 4: (2S, 3S) -3-((2- (6-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [ 2.2.2] Octane-2-carboxylic acid 3-((2- (6-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] in THF / MeOH (v / v = 8 mL / 4 mL)) ] To a solution of pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl (240 mg, 0.37 mmol) A solution of NaOH (150 mg, 3.75 mmol) in water (2 mL) was added. The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (150 mg, 87%).
MS (ESI, pos.ion) m / z: 458.1 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 458.2003 [M + H] ⁺ , (C ₂₆ H ₂₅ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 458.1992;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.36-12.25 (m, 1H), 12.21 (s, 1H), 9.03 (s, 1H), 8.23 (S, 1H), 8.12 (s, 2H), 7.61-7.48 (m, 4H), 7.00 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H) ), 4.62 (s, 1H), 1.99 (s, 3H), 1.69 (m, 8H).

  Example 76: (+/-)-trans-3-((5-fluoro-2- (6-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-((5-Fluoro-2- (6-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl THF (10 mL) was added to 6-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (517 mg, 0.49 mmol, 40%), potassium carbonate (262 mg, 1.89 mmol) ), Palladium acetate (21 mg, 0.09 mmol), XPhos (90 mg, 0.18 mmol) and 3-((2-chloro-5-fluoro-6- (furan-2-yl) pyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (180 mg, 0.47 mmol) was added. H ₂ O (1 mL) was then added to the mixture and the mixture was heated to 80 ° C. and stirred for 12 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a pale yellow solid (240 mg, 79%).
MS (ESI, pos.ion) m / z: 634.1 [M + H] ^< +>.

Step 2: (+/-)-trans-3-((5-fluoro-2- (6-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2- (6) in THF / MeOH (v / v = 8 mL / 4 mL) -Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of -2-carboxylic acid (+/-)-trans-methyl (240 mg, 0.38 mmol) was added a solution of NaOH (150 mg, 3.75 mmol) in water (2 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 3-4. The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to remove the solvent and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a white solid. (150 mg, 85%).
MS (ESI, pos.ion) m / z: 466.3 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 466.1702 [M + H] ⁺ , (C ₂₄ H ₂₂ F ₂ N ₅ O ₃ ) [M + H] ⁺ Theoretical: 466.1691;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.29 (s, 1H), 12.20 (s, 1H), 8.96 (t, J = 8.4 Hz, 1H), 8 .09 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.61 (d, J = 6.8 Hz, 1H), 7.27 (s, 1H), 7.00 (D, J = 8.4 Hz, 1H), 6.77 (s, 1H), 4.67 (s, 1H), 2.86 (d, J = 6.8 Hz, 1H), 2.01 (s , 1H), 1.97 (s, 1H), 1.78 (s, 3H), 1.65 to 1.39 (m, 5H).

  Example 77: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (isoxazole-5- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 1- (2,6-Dichloro-5-fluoropyrimidin-4-yl) ethanone To a mixture of glacial acetic acid (40 mL) and sulfuric acid (64 mL, 1.5 mol / L) was added 2,4-dichloro-5- Fluoropyrimidine (2.00 g, 12.00 mmol) was added. Acetaldehyde aqueous solution (16 mL, 100 mmol, 40% wt) was added to the mixture, and then ammonium sulfate (24 mL, 24 mmol, 1 mol / L) and ferrous sulfate (24 mL, 36 mmol, 1.5 mol / L) were continuously added dropwise. . The resulting mixture was stirred at 10 ° C. for 2 h. The mixture was filtered to give the title compound as an off-white solid (436 mg, 17%).
MS (ESI, pos.ion) m / z: 210.9 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.72 (s, 3H).

Step 2: 3-((6-Acetyl-2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl THF 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (53 mg, 0.29 mmol) and 1- (2,6-dichloro-5-) in (5 mL). To a solution of fluoropyrimidin-4-yl) ethanone (50 mg, 0.24 mmol) was added DIPEA (0.2 mL, 0.96 mmol) and the mixture was stirred at rt overnight. The mixture was diluted with water (40 mL) and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and dried. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (33 mg, 39%).
MS (ESI, pos.ion) m / z: 356.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.56 (s, 1H), 4.51 (s, 1H), 3.78 (s, 3H), 2.62 (s, 3H), 2.40 (d, J = 5.8 Hz, 1H), 2.03 (s, 1H), 1.90 (s, 1H), 1.67 (d, J = 11.0 Hz, 8H).

Step 3: 3-((2-Chloro-6-((E) -3- (dimethylamino) acryloyl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2- Carboxylic acid (+/−)-trans-methyl 3-((6-acetyl-2-chloro-5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] in DMF-DMA (1 mL) A solution of octane-2-carboxylic acid (+/−)-trans-methyl (33 mg, 0.09 mmol) was stirred at rt overnight. Water (25 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (25 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a yellow oil (33 mg, 87%).
MS (ESI, pos.ion) m / z: 411.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.84 (s, 1H), 5.87 (s, 1H), 5.46 (s, 1H), 4.49 (s, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 2.97 (s, 3H), 2.40 (d, J = 5.8 Hz, 1H), 2.01 (s, 1H) 1.89 (s, 1H), 1.67 (s, 8H).

Step 4: 3-((2-Chloro-5-fluoro-6- (isoxazol-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/- ) -Trans-methyl 3-((2-chloro-6-((E) -3- (dimethylamino) acryloyl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2. 2.2] To a solution of octane-2-carboxylic acid (+/-)-trans-methyl (200 mg, 0.4867 mmol) was added hydroxylammonium chloride (67 mg, 0.96 mmol). The reaction mixture was stirred at 78 ° C. overnight. The mixture was concentrated in vacuo to remove the solvent and the residue was dissolved in ethyl acetate (20 mL). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a red solid (35 mg, 19%).
MS (ESI, pos.ion) m / z: 381.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.40 (d, J = 1.6 Hz, 1H), 6.99 (s, 1H), 5.63 (d, J = 3.8 Hz, 1H), 4.55 (t, J = 4.9 Hz, 1H), 3.78 (s, 3H), 2.45 (d, J = 5.8 Hz, 1H), 2.04 (d, J = 2.2 Hz, 1H), 1.93 (d, J = 2.2 Hz, 1H), 1.77-1.60 (m, 8H).

Step 5: 3-((5-Fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (isoxazol-5-yl) pyrimidine- 4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl in a microwave tube, 5-fluoro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (170 mg, 0.25 mmol), 3-((2-chloro-5-fluoro- 6- (Isoxazol-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (78 mg, 0.21 mmol), water ( 0.2 mL), 1, 4 -Dioxane (3 mL), potassium carbonate (84 mg, 0.61 mmol) and XPhos (19 mg, 0.04 mmol) were added. Air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 3 h. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 2/1) to give the title compound as a yellow oil (28 mg, 22% ).
MS (ESI, pos.ion) m / z: 637.2 [M + H] ^< +>.

Step 6: (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (isoxazole-5- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((5-fluoro-2-) in THF / MeOH (v / v = 1/1, 2 mL) (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (isoxazol-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2 To a solution of octane-2-carboxylic acid (+/−)-trans-methyl (27 mg, 0.04 mmol) was added aqueous sodium hydroxide (4M, 0.10 mL, 0.40 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 5.5, and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (15 mg, 76%).
MS (ESI, pos.ion) m / z: 467.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 467.1644 [M + H] ⁺ , (C ₂₃ H ₂ 1F ₂ N ₆ O ₃ ) [M + H] ⁺ Theoretical: 467.1633;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.39 (s, 1H), 9.19 (s, 1H), 8.53 (d, J = 9.5 Hz, 1H), 8 .33 (s, 1H), 8.30 (s, 1H), 7.88 (d, J = 6.2 Hz, 1H), 7.24 (s, 1H), 4.75 (s, 1H), 2.89 (s, 1H), 2.03 (s, 1H), 1.87-1.73 (m, 3H), 1.70-1.42 (m, 6H).

  Example 78: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride The title compound can be prepared according to the synthetic method disclosed in patent application WO20150473491.

Step 2: 3-((2-Chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -Ethyl 3-aminobicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl hydrochloride (458 mg, 1.96 mmol), 2,4-dichloro- in dichloromethane (15 mL) To a solution of 7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine (410 mg, 1.78 mmol) was slowly added DIPEA (0.97 mL, 5.88 mmol). The mixture was stirred overnight at 30 ° C. under nitrogen protection. The reaction mixture was washed sequentially with water (10 mL), 5% aqueous sodium bisulfate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a yellow solid (333 mg, 50%).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidine -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2S, 3S) -ethyl 1,4-dioxane (3 mL) to 5-fluoro-3- (4,4,5,5). 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (284 mg, 0.31 mmol, 45% wt), potassium carbonate (106 mg, 0.77 mmol), PdCl ₂ (dppf) (41 mg, 0.05 mmol) and 3-((2-chloro-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [ 2. .2] octane-2-carboxylic acid (2S, 3S) - was added ethyl (100mg, 0.26mmol). H ₂ O (0.2 mL) was then added to the mixture and the air in the mixture was removed by bubbling with nitrogen for 10 min. The mixture was stirred at 110 ° C. with microwave heating for 2 h. The mixture was filtered to remove solid impurities. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1 to 5/1) to give the title compound as a white solid (146 mg, 89% ).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.73 (dd, J = 9.1, 2.7 Hz, 1H), 8.66 (s, 1H), 8.32 (s, 1H) 8.13 (d, J = 8.2 Hz, 2H), 7.30 (s, 2H), 7.06 (d, J = 3.5 Hz, 1H), 6.41 (d, J = 2. 9 Hz, 1H), 4.90 (s, 1H), 2.45 (d, J = 5.2 Hz, 1H), 2.38 (s, 3H), 2.08 (s, 2H), 2.00 -1.66 (m, 8H), 1.57 (d, J = 6.7 Hz, 6H), 1.28 (s, 5H).

Step 4: (2S, 3S) -3-((2- (5-Fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d ] Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-) in THF / MeOH (v / v = 5 mL / 5 mL) Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane To a solution of 2-carboxylic acid (2S, 3S) -ethyl (146 mg, 0.23 mmol) was added a solution of NaOH (90 mg, 2.26 mmol) in water (1 mL). The mixture was stirred at rt overnight and then diluted with water (10 mL). The resulting mixture was acidified with hydrochloric acid (1M) to pH ˜6. The resulting mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated in vacuo to remove the solvent and the residue is purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1 to 5/1) to give the title compound as a yellow solid. (65 mg, 62%).
MS (ESI, pos.ion) m / z: 463.4 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 463.2264 [M + H] ⁺ , (C25H ₂₈ FN ₆ O ₂ ) [M + H] ⁺ Theoretical: 4633.2258;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (s, 1 H), 12.08 (s, 1 H), 8.68 (d, J = 8.8 Hz, 1 H), 8 .26 (s, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 2.5 Hz, 2H), 6.64 (s, 1H), 5.02 (M, 1H), 4.79 (s, 1H), 2.72 (d, J = 6.3 Hz, 1H), 2.03 (d, J = 12.3 Hz, 2H), 1.79 (m , 3H), 1.54 (m, 11H).

  Example 79: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-morpholinophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 4- (4- (2,6-Dichloropyrimidin-4-yl) phenyl) morpholine To a solution of 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol) in tetrahydrofuran (8.18 mL), Palladium acetate (63 mg, 0.28 mmol), triphenylphosphine (150 mg, 0.548 mmol), (4-morpholinophenyl) boronic acid (570 mg, 2.75 mmol) and aqueous sodium carbonate (1M, 8.18 mL, 8.18 mmol) ) Was added. The mixture was stirred at 70 ° C. for 6 h under nitrogen protection, then water (50 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE) to give the title compound as a white solid (374 mg, 44%).
MS (ESI, pos.ion) m / z: 310.0 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.04 (d, J = 9.1 Hz, 2H), 7.56 (s, 1H), 6.96 (d, J = 9.1 Hz, 2H), 3.92-3.88 (m, 4H), 3.37-3.33 (m, 4H).

Step 2: 3-((2-Chloro-6- (4-morpholinophenyl) pyrimidin-4-yl) amino) cycle [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 3-Aminobicyclo [2.2.2] octane-2-carboxylic acid (+/−)-trans-methyl (230 mg, 1.25 mmol) and 4- (4- (2,6-) in DMF (5 mL) To a solution of dichloropyrimidin-4-yl) phenyl) morpholine (353 mg, 1.14 mmol) was added potassium carbonate (173 mg, 1.25 mmol) and the mixture was stirred at rt overnight. Water (40 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was purified by silica gel column chromatography (PE / EA (v / v) = 20/1) to give the title compound as a white solid (192 mg, 37%) .
MS (ESI, pos.ion) m / z: 457.3 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.96 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.71 (s, 1H), 5.41-5.34 (m, 1H), 4.32 (s, 1H), 3.92-3.86 (m, 4H), 3.75 (s, 3H), 3.32 −3.25 (m, 4H), 2.39 (d, J = 4.8 Hz, 1H), 2.07 (d, J = 3.3 Hz, 1H), 1.88 (d, J = 2. 7Hz, 1H), 1.81-1.62 (m, 6H), 1.53-1.41 (m, 2H).

Step 3: 3-((2- (5-Fluoro-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-morpholinophenyl) pyrimidin-4-yl) amino ) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl 5-fluoro-3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (396 mg, 0.38 mmol), 3-((2-chloro-6- (4-morpholinophenyl) Pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (145 mg, 0.32 mmol), potassium carbonate (131 mg, 0.95 mmol), Pd (Dp _{pf) Cl 2 (51mg, 0.06mmol} ), was added 1,4-dioxane (3 mL) and water (0.2 mL). Air in the mixture was removed by bubbling with nitrogen for 10 min, and the mixture in a sealed tub container was stirred at 110 ° C. for 2 h. The reaction mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (148 mg, 66%) .
MS (ESI, pos.ion) m / z: 712.2 [M + H] ⁺ ;
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.71 (dd, J = 8.1, 3.6 Hz, 2H), 8.33 (d, J = 1.8 Hz, 1H), 8. 13 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.30 (s, 2H), 7.04 (d, J = 8.9 Hz, 2H) ), 6.67 (s, 1H), 5.12 (s, 1H), 4.52 (s, 1H), 3.96-3.87 (m, 4H), 3.35-3.26 ( m, 4H), 2.45 (d, J = 4.9 Hz, 1H), 2.39 (s, 3H), 2.10 (s, 1H), 1.98 (s, 1H), 1.84. (D, J = 10.1 Hz, 2H), 1.69 (m, 6H).

Step 4: (+/-)-trans-3-((2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-morpholinophenyl) pyrimidine-4 -Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-1-tosyl-) in THF / MeOH (v / v = 1/1, 3 mL) 1H-pyrrolo [2,3-b] pyridin-3-yl) -6- (4-morpholinophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+ / To a solution of −)-trans-methyl (144 mg, 0.20 mmol) was added aqueous sodium hydroxide (4M, 0.5 mL, 2 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (10 mL). The resulting mixture was acidified to pH 5.5 with hydrochloric acid (1M) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (36 mg, 33%).
MS (ESI, pos.ion) m / z: 543.2 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 543.2513 [M + H] ⁺ , (C ₃₀ H ₃₂ FN ₆ O ₃ ) [M + H] ⁺ Theoretical: 543.2520;
¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 12.24 (s, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H) ), 8.01 (s, 2H), 7.33 (s, 1H), 7.09 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 4.63 (s, 1H), 4.03 (d, J = 7.0 Hz, 1H), 3.77 (s, 4H), 3.60 (s, 1H), 3.24 (s, 4H), 1.93-1 .29 (m, 10H).

  Example 80: (+/-)-trans-3-((2- (5-fluoro-6-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1: 3-Bromo-5-fluoro-6-methylpyridin-2-amine To a solution of 5-fluoro-6-methylpyridin-2-amine (1.55 g, 12.3 mmol) in acetonitrile (16 mL), NBS (2.83 g, 15.9 mmol) was added in portions at −5 ° C. After the addition, the mixture was stirred at −5 ° C. for 1.5 h. To the mixture was added ethyl acetate (80 mL) and the resulting mixture was washed with water (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 10/1 to 3/1) to give the title compound as a pale yellow solid ( 1.72 g, 68%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.41 (d, J = 7.9 Hz, 1H), 4.78 (s, 2H), 2.34 (d, J = 2.9 Hz, 3H).

Step 2: 5-Fluoro-6-methyl-3-((trimethylsilyl) ethynyl) pyridin-2-amine 3-Bromo-5-fluoro-6-methylpyridin-2-amine (1.50 g, 7 .32 mmol), bis (triphenylphosphine) palladium (II) chloride (513 mg, 0.73 mmol), cuprous iodide (263 mg, 1.38 mmol), triethylamine (6.0 mL, 43.2 mmol) and tetrahydrofuran (1 0.0 mL) was added. To the mixture, trimethylsilylacetylene (1.95 mL, 13.8 mmol) was slowly added dropwise at rt under nitrogen protection, and the resulting mixture was heated to 50 ° C. and stirred for 4 h. The reaction mixture was cooled to room temperature and saturated aqueous ammonium chloride (30 mL) was added. The resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 15/1 to 4/1) to give the title compound as a gray solid (1.30 g). 80%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.23 (d, J = 9.1 Hz, 1H), 4.84 (s, 2H), 2.37 (d, J = 2.9 Hz, 3H), 0.28 (s, 9H).

Step 3: 5-Fluoro-6-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine To a suspension of potassium tert-butoxide (855 mg, 7.62 mmol) in NMP (15 mL) Fluoro-6-methyl-3-((trimethylsilyl) ethynyl) pyridin-2-amine (1.30 g, 5.85 mmol) was added in small portions at 50 ° C. After the addition, the mixture was heated to 80 ° C. under nitrogen protection and stirred for 3 h. The reaction mixture was cooled to rt and TsCl (1.35 g, 7.08 mmol) was added in small portions to the reaction mixture. After the addition, the mixture was stirred at 30 ° C. for 2 h. Water (40 mL) was added to the mixture and the resulting mixture was filtered. The filter cake was purified by silica gel column chromatography (PE / EtOAc (v / v) = 20 / 1-6 / 1) to give the title compound as a white solid (820 mg, 46%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.11 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 3.9 Hz, 1H), 7.44 (d, J = 9.3 Hz, 1H), 7.31 (s, 2H), 6.51 (d, J = 4.0 Hz, 1H), 2.61 (d, J = 3.2 Hz, 3H), 2. 40 (s, 3H).

Step 4: 3-Bromo-5-fluoro-6-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine 5-fluoro-6-methyl-1-tosyl-1H-in DMF (8 mL) A solution of pyrrolo [2,3-b] pyridine (590 mg, 1.94 mmol) was cooled to 0 ° C. and bromine (0.3 mL, 6 mmol) was slowly added dropwise to the solution. After the addition, the mixture was stirred at rt for 2 h. The mixture was added dropwise to saturated aqueous sodium thiosulfate (30 mL) and the resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a yellow solid (468 mg, 63%).
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.10 (d, J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 2.63 (d, J = 3.2 Hz, 3H), 2.41 (s, 3H).

Step 5: 5-Fluoro-6-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3- b] Pyridine In a microwave vessel 3-bromo-5-fluoro-6-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridine (468 mg, 1.23 mmol), bis (pinacolato) diboron (483 mg, 1.90 mmol), potassium acetate (248 mg, 2.53 mmol), Pd (dppf) Cl ₂ (95 mg, 0.13 mmol) and DME (5 mL) were added. After removing air in the mixture by bubbling with nitrogen for 10 min, the mixture was stirred at 130 ° C. for 2 h with microwave heating. The reaction mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated in vacuo and the residue was used in the next step without further purification.
MS (ESI, pos.ion) m / z: 431.1 [M + H] ^< +>.

Step 6: 3-((2- (5-Fluoro-6-methyl-1-tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) Bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl In a microwave vessel, 5-fluoro-6-methyl-3- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b] pyridine (187 mg, 0.26 mmol, 60%), 3-((2-chloro-6-phenylpyrimidine) -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-)-trans-methyl (80 mg, 0.22 mmol), potassium carbonate (89 mg, 0.65 mmol), Pd ( dppf) Cl (35mg, 0.04mmol), was added 1,4-dioxane (3 mL) and water (0.2 mL). Air in the mixture was removed by bubbling with nitrogen for 10 min, and the mixture in a sealed tub container was stirred at 110 ° C. for 3 h. The mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane / EtOAc (v / v) = 2/1) to give the title compound as a yellow solid (77 mg, 56%). .
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.64 (s, 1H), 8.57 (d, J = 9.9 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 8.11 (d, J = 6.8 Hz, 2H), 7.54 (dd, J = 14.6, 7.0 Hz, 3H), 7.39 (d, J = 4.3 Hz, 1H) ), 7.31 (s, 1H), 6.73 (s, 1H), 5.18 (s, 1H), 4.54 (s, 1H), 3.74 (s, 3H), 2.64 (D, J = 3.0 Hz, 3H), 2.45 (d, J = 4.8 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 1H), 1.99 (s) , 1H), 1.92-1.62 (m, 8H).

Step 7: (+/-)-trans-3-((2- (5-fluoro-6-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidine-4- Yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid 3-((2- (5-fluoro-6-methyl-1) in THF / MeOH (v / v = 1/1, 3 mL) -Tosyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (+/-) To a solution of trans-methyl (77 mg, 0.12 mmol) was added aqueous sodium hydroxide solution (4M, 0.30 mL, 1.20 mmol). The mixture was stirred at 30 ° C. overnight and then diluted with water (20 mL). The resulting mixture was acidified with hydrochloric acid (1M) to a pH of about 5.5, and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10/1) to give the title compound as a yellow solid (25 mg, 44%).
MS (ESI, pos.ion) m / z: 472.5 [M + H] ⁺ ;
HRMS (ESI, pos.ion) m / z: 472.2156 [M + H] ⁺ , (C ₂₇ H ₂₇ FN ₅ O ₂ ) [M + H] ⁺ Theoretical value: 472.2149;
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.31 (s, 1H), 12.07 (s, 1H), 8.55 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.10 (s, 2H), 7.60-7.38 (m, 4H), 6.76 (s, 1H), 4.64 (s, 1H), 2. 53 (d, J = 2.5 Hz, 4H), 1.99 (s, 2H), 1.86-1.39 (m, 8H).

Examples of biological assays In the following examples, using some of the compounds of the invention as examples, we detect the antiviral and cytotoxic activities and pharmacokinetic properties of the compounds of the invention. did.

Example A: Cytopathic effect assay (CPE assay)
Detection of the inhibitory effect of the compounds of the invention on the cytopathic effect (CPE) of the virus H1N1 A / Weiss / 43 at the cellular level in vitro.

Scheme 1: MDCK cells (Madin, Derby, canine kidney cells) were seeded in 384 well plates at 2000 cells / well and cultured overnight at 37 ° C., 5% CO ₂ . The next day, the cell culture medium is fresh medium containing the appropriate concentration of test compound and the virus H1N1A / Weiss / 43, giving a multiplicity of infection that yields 80-95% CPE (or titer 1 TCID90 / well). Replenished with. The maximum final concentration of test compound is 100 μM, followed by a total of 8 concentrations: 100 μM, 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.05 μM. Was serially diluted 3-fold. The test conditions of the cytotoxicity test group are the same as above except that the cell culture solution of the cytotoxicity test group does not contain influenza virus. A virus control group containing no drug and a cell control group not infected with a virus containing no drug were set at the same time. Each group was set up in duplicate and incubated at 37 ° C. for 5 days under 5% CO ₂ . Cell activity was detected using the CCK-8 kit, and the data was used to calculate the antiviral effect and cytotoxicity of the compounds on virus-infected cells. Data was analyzed using GraphPad Prism software to calculate CPE inhibition and cell viability. EC ₅₀ and CC ₅₀ values were obtained according to curve fitting.

CPE inhibition rate = [(absorbance of dosing well−absorbance of virus control well) / (absorbance of cell control well−absorbance of virus control well)] × 100%
Cell viability = [(absorbance of dosing well−absorbance of medium control well) / (absorbance of cell control well−absorbance of medium control well)] × 100%
Table 1 shows the inhibitory activity of the compounds of the present invention against influenza virus (A / Weiss / 43 (H1N1)).

  This assay shows that the compounds of the invention have excellent anti-influenza virus activity.

Scheme 2: MDCK cells (Madin Derby canine kidney cells) were seeded at 2,000 wells / well in 384 well plates and cultured overnight at 37 ° C., 5% CO ₂ . The next day, the cell culture medium is reconstituted with fresh medium containing the appropriate concentrations of test compound and virus H1N1A / Weiss / 43 to obtain a multiplicity of infection that gives 80-95% CPE (or titer 1 TCID90 / well). Replenished with. The maximum final concentration of test compound is 50 nM, followed by a total of 8 concentrations: 50 nM, 16.67 nM, 5.56 nM, 1.85 nM, 0.62 nM, 0.21 nM, 0.068 nM, 0.023 nM. Was serially diluted 3-fold. The test conditions of the cytotoxicity test group are the same as above except that the cell culture solution of the cytotoxicity test group does not contain influenza virus. A virus control group containing no drug and a cell control group not infected with the virus containing no drug were placed at the same time. Each group was set up in duplicate and incubated at 37 ° C. for 5 days under 5% CO ₂ . Cell activity was detected using the CCK-8 kit, and the data was used to calculate the antiviral effect and cytotoxicity of the compounds on virus-infected cells. Data was analyzed using GraphPad Prism software to calculate CPE inhibition and cell viability. EC ₅₀ and CC ₅₀ values were obtained according to curve fitting.

CPE inhibition rate = [(absorbance of dosing well−absorbance of virus control well) / (absorbance of cell control well−absorbance of virus control well)] × 100%
Cell viability = [(absorbance of dosing well−absorbance of medium control well) / (absorbance of cell control well−absorbance of medium control well)] × 100%
Table 2 shows the inhibitory activity of the compounds of the present invention against influenza virus (A / Weiss / 43 (H1N1)).

  This assay shows that the compounds of the invention have excellent anti-influenza virus activity.

  Example B: Pharmacokinetic evaluation after a specific amount of a compound of the invention has been administered intravenously or orally to rats, dogs or monkeys.

  The pharmacokinetic properties of the compounds of the present invention and control compound VX-787 (also referred to as JNJ-872, the structure shown below) in SD rats, dogs or monkeys were evaluated. The compounds disclosed herein were administered in the form of a saline solution containing 5% DMSO, 5% Kolliphor HS 15 and 90% saline. In the case of intravenous administration (iv), animals are administered at a dose of 1 mg / kg and a blood sample (0.3 mL) is administered and then 0.083, 0.25, 0.5, 1.0, 2.0. Each blood sample was processed to separate plasma by centrifugation at 3000 rpm or 4000 rpm for 10 minutes after collection at time points 5.0, 7.0 and 24 h. In the case of oral administration (po), animals are administered at a dose of 5 mg / kg, and blood samples (0.3 mL) are dosed and then 0.25, 0.5, 1.0, 2.0, 5.0, After collection at 7.0 and 24 h, each blood sample was processed to separate plasma by centrifugation at 3000 rpm or 4000 rpm for 10 minutes. Plasma samples were collected and stored at -20 ° C or -70 ° C until LC / MS / MS analysis.

  This assay shows that the compounds of the invention have high exposure levels and excellent absorption in animals in vivo, and that the pharmacokinetic properties of the compounds of the invention have significant advantages.

  Table 3 shows the pharmacokinetic data of the compounds of the invention in vivo in SD rats.

Note: Control compound ... (+/-)-trans-3-((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b] pyridin-3-yl) pyrimidin-4-yl) Amino) bicyclo [2.2.2] octane-2-carboxylic acid (detailed synthetic procedures can be found in patent WO2010148197),
AUC _last ... 0-24h AUC,
AUC _INF : AUC of 0 to infinite time.

Table 3 shows that the C _max , AUC _last and AUC _INF of the compounds of the invention in SD rats were higher than those of compound VX-787, both intravenously and orally. This indicates that the compounds of the present invention have high exposure levels and excellent absorption in SD rats, and the pharmacokinetic properties of the compounds of the present invention are significantly superior to the control compound VX-787. Represents.

  Throughout this specification "one embodiment", "some embodiments", "one embodiment", "other examples", "some examples", "specific examples" or "some examples" It is meant that any particular feature, structure, material, or property described in connection with that embodiment or example is included in at least one embodiment or example of this disclosure. Thus, in various places herein, “in some embodiments,” “in one embodiment,” “in one embodiment,” “in another example,” “in an example,” “ The appearance of a phrase such as “in an example” or “in some examples” does not necessarily refer to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

  While exemplary embodiments have been shown and described, the above embodiments are not intended to limit the present disclosure, and changes, substitutions, and modifications in the embodiments may be made without departing from the spirit, principles, and scope of the present disclosure. It will be appreciated by those skilled in the art that

Claims (26)

A compound having the formula (I), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

Where
Each R ¹ and R ³ is independently H, F, Cl, Br, CN, NO ₂ , —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N—C _1-4 alkylene, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _1-4 alkylene, C _{6 -10} aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl or (5 to 10 membered heteroaryl) -C _1-4 alkylene, wherein C _{1-6 alkyl, C 2-6} alkenyl, _{2-6 alkynyl, C 3-8 cycloalkyl, C 3-8} cycloalkyl _{-C 1-4} alkylene, from 3-membered to 12-membered heterocyclyl, (from 3-membered to 12-membered _{heterocyclyl) -C 1-4} alkylene , C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl and (5 to 10 membered heteroaryl) -C _1-4 alkylene are each Independently, unsubstituted, F, Cl, Br, CN, OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O—C _1-4 alkylene or R substituted with one, two, three or four substituents independently selected from ^d R ^c N—C _1-4 alkylene;
n is 0, 1, 2 or 3;
Each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkylene, 3 to 12 membered heterocyclyl, (from 3 membered 12-membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 membered heteroaryl, (5 to 14 membered heteroaryl) Aryl) -C _1-4 alkylene, or two adjacent R ^{2 s} , together with the atoms to which they are attached, a C _3-12 carbocyclic ring, 3 to 12 membered heterocycle Forming a formula ring, a C _6-10 aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkyl Rene, 3 to 12 membered heterocyclyl, (3 to 12 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 14 Up to 6-membered heteroaryl, (5- to 14-membered heteroaryl) -C _1-4 alkylene, C _3-12 carbocyclic ring, 3 to 12-membered heterocyclic ring, C _6-10 aromatic Each of the ring and 5- to 10-membered heteroaromatic ring is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that When m is 1, R ² is not F,
Each R ′ is independently F, Cl, Br, CN, NO ₂ , ═O, OR ^b , —NR ^c R ^d , R ^b O—C _1-4 alkylene, R ^d R ^c N—C _{1 — 4} alkylene, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , C _1-10 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl , C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _1-4 alkylene, C _6-10 aryl, C _6-10 Aryl-C _1-4 alkylene, 5- to 6-membered heteroaryl or (5- to 6-membered heteroaryl) -C _1-4 alkylene, wherein C _1-10 alkyl, C _{1- 6 haloalkyl, C 3-6 cycloalkyl, C 3-} Cycloalkyl _{-C 1-4} alkylene, heterocyclyl from 3-membered to 6-membered, (from 3-membered to 6-membered _{heterocyclyl) -C 1-4 alkylene, C 6-10 aryl, C 6-10} aryl _{-C 1-} Each of _4- alkylene, 5- to 6-membered heteroaryl and (5- to 6-membered heteroaryl) -C _1-4 alkylene is independently unsubstituted or F, Cl, Br, Independently from CN, NO ₂ , OR ^b , —NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, R ^b O—C _1-4 alkylene or R ^d R ^c N—C _1-4 alkylene Substituted with one, two, three or four selected substituents;
m is 1 or 2,
X has one of the following subformulae:

Wherein R ⁴ is H or C _1-6 alkyl, and the C _1-6 alkyl may be optionally substituted with 1, 2, 3, or 4 U;
Each R ⁵ , R ⁶ , R ⁷ and R ⁸ is independently H or C _1-6 alkyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached, C _{3 A -8} cycloalkyl group, a 3 to 6 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring, or R ⁷ and R ⁸ are Together with the nitrogen atom to which it is attached, it forms a 3- to 6-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, C _1-6 alkyl, C _3-8 cycloalkyl, 3 Each of the 6 to 6 membered heterocyclic ring, the C _6-10 aromatic ring or the 5 to 10 membered heteroaromatic ring is independently unsubstituted or 1, 2, 3 , Or 4 U's,
W is a C _3-12 carbocyclic ring or a 3 to 12 membered heterocyclic ring;
Each V and V ′ is independently a C _3-12 cycloalkane ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring;
Each R ^w is independently F, Cl, Br, CN, NO ₂ , ═O, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^{d. _{, -S (= O) 2 R}} e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, (R b O) 2 P (= O ) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, C _1-6 alkyl, 5 to 6 members Up to heteroaryl or 5- to 6-membered heterocyclyl, wherein each of C _1-6 alkyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl is independently Is unsubstituted or substituted with 1, 2, 3, or 4 U;
Each U is independently F, Cl, Br, NO ₂ , CN, ═O, N ₃ , OR ^b , —NR ^c R ^d , C _1-6 alkyl or C _1-6 haloalkyl;
Each s and t is independently 0, 1, 2 or 3,
p is 1, 2 or 3, and each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _{1 -4} alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene Or R ^c and R ^d together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic ring, wherein C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkini , C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, 3 to 6 membered heterocyclyl, (3 to 6 membered heterocyclyl) -C _1-4 alkylene, C _{6 -10} aryl, C _6-10 aryl-C _1-4 alkylene, 5 to 10 membered heteroaryl, (5 to 10 membered heteroaryl) -C _1-4 alkylene and 3 to 6 membered each heterocyclic ring, independently, either unsubstituted, or _{F, Cl, CN, OH,} NH 2, C 1-6 _{alkyl, C 1-6 haloalkyl, C 1-6} alkoxy or _{C 1} Substituted with 1, 2, 3, or 4 substituents independently selected from _-6 alkylamino. 2. A compound according to claim 1 having the formula (II).

_Where A is a C _3-12 carbocyclic ring, a 3 to 12 membered heterocyclic ring, a C _6-10 aromatic ring or a 5 to 10 membered heteroaromatic ring, and q is , 0, 1, 2, 3, 4 or 5. Each R ¹ and R ³ is independently H, F, Cl, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^d , OR ^b , — NR ^c R ^d , C _1-3 alkyl, C _3-6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, wherein C _1-3 alkyl, Each of C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl is independently unsubstituted or F, Cl, OR ^b , —NR substituted with 1, 2, 3 or 4 substituents independently selected from ^c R ^d , C _1-3 alkyl, C _1-3 haloalkyl or R ^b O—C _1-2 alkylene, The compound according to claim 1 or 2. Each R ² is independently F, C _2-6 alkynyl, OR ^b , C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 to 6 membered heterocyclyl, (from 5 member to 6-membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5 to 6 membered heteroaryl, (5 to 6 membered heteroaryl) -C _1- or is ₂ alkylene or two R ² adjacent, together with the atom to which they are attached, C _5-6 carbocyclic ring, heterocyclic ring from 5-membered to 6-membered benzene ring or Forms a 5- to 6-membered heteroaromatic ring, wherein C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, 5 to 6-membered heterocyclyl, (5 to 6 membered heterocyclyl) -C _1-2 alkylene, phenyl, naphthyl, phenyl-C _1-2 alkylene, 5 to 6 membered heteroaryl, (5 to 6 membered heteroaryl) -C _1-2 alkylene, C _5-6 carbocyclic ring, 5- to 6-membered heterocyclic ring, benzene ring and 5- to 6-membered heteroaromatic ring are each independently unsubstituted 2. The compound of claim 1, wherein the compound is or is substituted with 1, 2, 3, 4 or 5 R ', provided that when m is 1, R ² is not F. Each R ′ is independently F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , —C (═O) R ^a , —C (═O) NR ^c R ^d , C _{1. -9} alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene or 5 to 6 membered heteroaryl, wherein Each of C _1-9 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 5 to 6 membered heterocyclyl, phenyl, phenyl-C _1-4 alkylene and 5 to 6 membered heteroaryl Are independently unsubstituted or independently selected from F, Cl, Br, CN, NO ₂ , OR ^b , —NR ^c R ^d , methyl, ethyl, n-propyl or i-propyl One, two, three 3. A compound according to claim 1 or 2 which is substituted with one or four substituents. Each R ^a , R ^b , R ^c , R ^d and R ^e is independently H, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _1-3 haloalkyl, C _{3 -6} cycloalkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene, or R ^c and R ^d are Together with the attached nitrogen atom, it forms a 5- to 6-membered heterocyclic ring, methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, C _3-6 cyclo Each of the alkyl, C _3-6 cycloalkyl-C _1-2 alkylene, 3 to 6 membered heterocyclyl, phenyl, phenyl-C _1-2 alkylene and 5 to 6 membered heterocyclic ring is independently No 1, 2, 3, or 4 substituents that are substituted or independently selected from F, Cl, CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl or methoxy 3. A compound according to claim 1 or 2 substituted with X has one of the following subformulae:

_Where W is a C _6-8 carbocyclic ring or a 6 to 8 membered heterocyclic ring;
Each V and V ′ is independently a C _3-8 cycloalkane ring, a 3 to 8 membered heterocyclic ring, a benzene ring or a 5 to 6 membered heteroaromatic ring;
Each R ^w is independently F, Cl, Br, CN, NO ₂ , ═O, —C (═O) R ^a , —C (═O) OR ^b , —C (═O) NR ^c R ^{d. _{, -S (= O) 2 R}} e, -S (= O) 2 NR c C (= O) R a, -S (= O) 2 NR c R d, (R b O) 2 P (= O ) —C _0-2 alkylene, OR ^b , —NR ^c R ^d , R ^b O—C _1-2 alkylene, R ^d R ^c N—C _1-2 alkylene, methyl, ethyl, i-propyl, n-propyl , N-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyrazolyl, wherein methyl, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, tetrazolyl, isoxazolyl, oxazo Each of lyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and pyrazolyl is independently unsubstituted or substituted with 1, 2, 3, or 4 U And each U is independently F, Cl, Br, CF ₃ , NO ₂ , CN, ═O, N ₃ , OR ^b , —NR ^c R ^d , methyl, ethyl, i-propyl, n-propyl The compound according to claim 1, which is n-butyl or t-butyl. A compound according to claim 2, wherein A is a _C5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, a benzene ring, a naphthalene ring or a 5- to 6-membered heteroaromatic ring. Each R ² is independently F, ethynyl, propynyl, OR ^b , C _3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, furyl, benzofuryl, pyrrolyl, Pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxytinyl,

Where ethynyl, propynyl, C _3-6 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, naphthyl, phenyl-C _1-2 alkylene, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benz Imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxytinyl,

Each independently is substituted or substituted with 1, 2, 3, 4 or 5 R ′, provided that when m is 1, R ² is F 2. A compound according to claim 1 which is not. 8. The compound of claim 7, wherein X has one of the following subformulae:

A is a C _5-6 carbocyclic ring, a 5- to 6-membered heterocyclic ring, benzene, naphthalene, furan, benzofuran, pyrrole, pyridine, pyrazole, imidazole, benzimidazole, triazole, tetrazole, oxazole, oxa The compound according to claim 2, which is diazole, 1,3,5-triazine, thiazole, thiophene, benzothiophene, pyrazine, pyridazine, pyrimidine, indole, purine, quinoline or isoquinoline. 8. A compound according to claim 7 having the formula (III), (IV), (V), (VI), (VII) or (VIII).

The compound of claim 1 having one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

  A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1-13.   15. The pharmaceutical composition according to claim 14, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or combination thereof.   The pharmaceutical composition according to claim 14 or 15, further comprising one or more therapeutic agents, wherein the therapeutic agent is an anti-influenza virus agent or an anti-influenza virus vaccine.   The therapeutic agents are amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol, ribavirin, stakifurin, ingavirin, Fludase, CAS number 14222050-75-6, JNJ- The pharmaceutical composition according to claim 16, which is 872, AL-794, influenza vaccine or a combination thereof.   A compound according to any one of claims 1 to 13 or a claim 14 to 17 in the manufacture of a medicament for preventing, treating, treating or alleviating a disorder or disease resulting from a viral infection in a diseased body. Use of the pharmaceutical composition according to any one of the above.   The use according to claim 18, wherein the viral infection is an influenza virus infection.   Use of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17 in the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.   18. A compound according to any one of claims 1 to 13 or any of claims 14 to 17 for use in preventing, treating, treating or alleviating a disorder or disease resulting from a viral infection. 2. A pharmaceutical composition according to item 1.   The compound or pharmaceutical composition according to claim 21, wherein the viral infection is an influenza virus infection.   18. A compound according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17 for use in inhibiting RNA polymerase of influenza virus.   A viral infection in a diseased subject comprising administering to the diseased subject a therapeutically effective amount of a compound according to any one of claims 1-13 or a pharmaceutical composition according to any one of claims 14-17. A method of preventing, treating, treating, or alleviating a disorder or disease caused by the disease.   25. The method of claim 24, wherein the viral infection is an influenza virus infection.   An influenza virus in a afflicted subject comprising administering to the afflicted subject a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17. To inhibit the RNA polymerase.